Amidobenzamide derivatives which are useful as cytokine inhibitors

ABSTRACT

The invention concerns amide derivatives of the Formula (I) wherein R 3  is (1-6C)alkyl or halogeno; Q is aryl or heteroaryl which optionally bears 1, 2, 3 or 4 substituents such as hydroxy, halogeno, trifluoromethyl, cyano, (1-6C)alkyl, (1-6C)alkoxy, halogeno-(1-6C)alkyl, hydroxyl-(1-6C)alkyl, di-[(1-6C)akly]amino-(1-6C)alkyl, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, amino(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, aryl, aryl-(1-6C)alkoxy, heteroaryl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy; p is 0-2 and R 2  is a substituent such as hydroxy and halogeno; q is 0-4; and R 4  includes optionally substituted aryl, cycloalkyl, heteroaryl and heterocyclyl; or pharmaceutically-acceptable salts or in-vivo-cleavable esters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

This is a Divisional of application Ser. No. 09/762,106, filed Feb. 2,2001 (now U.S. Pat. No. 6,821,965), which is a PCT National Stage ofPCT/GB99/02494 filed Jul. 29, 1999, which claims priority to GreatBritain Application No. 9816837.0 filed Aug. 4, 1998.

This invention concerns certain amide derivatives which are useful asinhibitors of cytokine mediated disease. The invention also concernsprocesses for the manufacture of the amide derivatives of the invention,pharmaceutical compositions containing them and their use in therapeuticmethods, for example by virtue of inhibition of cytokine mediateddisease.

The amide derivatives disclosed in the present invention are inhibitorsof the production of cytokines such as Tumour Necrosis Factor(hereinafter TNF), for example TNFα, and various members of theinterleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8.Accordingly the compounds of the invention will be useful in thetreatment of diseases or medical conditions in which excessiveproduction of cytokines occurs, for example excessive production of TNFαor IL-1. It is known that cytokines are produced by a wide variety ofcells such as monocytes and macrophages and that they give rise to avariety of physiological effects which are believed to be important indisease or medical conditions such as inflammation and immunoregulation.For example, TNFα and IL-1 have been implicated in the cell signallingcascade which is believed to contribute to the pathology of diseasestates such as inflammatory and allergic diseases and cytokine-inducedtoxicity. It is also known that, in certain cellular systems, TNFαproduction precedes and mediates the production of other cytokines suchas IL-1.

Abnormal levels of cytokines have also been implicated in, for example,the production of physiologically-active eicosanoids such as theprostaglandins and leukotrienes, the stimulation of the release ofproteolytic enzymes such as collagenase, the activation of the immunesystem, for example by stimulation of T-helper cells, the activation ofosteoclast activity leading to the resorption of calcium, thestimulation of the release of proteoglycans from, for example,cartilage, the stimulation of cell proliferation and to angiogenesis.

Cytokines are also believed to be implicated in the production anddevelopment of disease states such as inflammatory and allergicdiseases, for example inflammation of the joints (especially rheumatoidarthritis, osteoarthritis and gout), inflammation of thegastrointestinal tract (especially inflammatory bowel disease,ulcerative colitis, Crohn's disease and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis, allergic rhinitis and adult respiratorydistress syndrome), and in the production and development of variouscardiovascular and cerebrovascular disorders such as congestive heartdisease, myocardial infarction, the formation of atheroscleroticplaques, hypertension, platelet aggregation, angina, stroke, reperfusioninjury, vascular injury including restenosis and peripheral vasculardisease, and, for example, various disorders of bone metabolism such asosteoporosis (including senile and postmenopausal osteoporosis), Paget'sdisease, bone metastases, hypercalcaemia, hyperparathyroidism,osteosclerosis, osteoperosis and periodontitis, and the abnormal changesin bone metabolism which may accompany rheumatoid arthritis andosteoarthritis. Excessive cytokine production has also been implicatedin mediating certain complications of bacterial, fungal and/or viralinfections such as endotoxic shock, septic shock and toxic shocksyndrome and in mediating certain complications of CNS surgery or injurysuch as neurotrauma and ischaemic stroke. Excessive cytokine productionhas also been implicated in mediating or exacerbating the development ofdiseases involving cartilage or muscle resorption, pulmonary fibrosis,cirrhosis, renal fibrosis, the cachexia found in certain chronicdiseases such as malignant disease and acquired immune deficiencysyndrome (AIDS), tumour invasiveness and tumour metastasis and multiplesclerosis.

Evidence of the central role played by TNFα in the cell signallingcascade which gives rise to rheumatoid arthritis is provided by theefficacy in clinical studies of antibodies of TNFα (The Lancet, 1994,344, 1125 and British Journal of Rheumatology, 1995, 34, 334).

Thus cytokines such as TNFα and IL-1 are believed to be importantmediators of a considerable range of diseases and medical conditions.Accordingly it is expected that inhibition of the production of and/oreffects of these cytokines will be of benefit in the prophylaxis,control or treatment of such diseases and medical conditions.

Without wishing to imply that the compounds disclosed in the presentinvention possess pharmacological activity only by virtue of an effecton a single biological process, it is believed that the compoundsinhibit the effects of cytokines by virtue of inhibition of the enzymep38 kinase. P38 kinase, otherwise known as cytokine suppressive bindingprotein (hereinafter CSBP) and reactivating kinase (hereinafter RK), isa member of the mitogen-activated protein (hereinafter MAP) kinasefamily of enzymes which is known to be activated by physiological stresssuch as that induced by ionising radiation, cytotoxic agents, andtoxins, for example endotoxins such as bacterial lipopolysaccharide, andby a variety of agents such as the cytokines, for example TNFα and IL-1.It is known that p38 kinase phosphorylates certain intracellularproteins which are involved in the cascade of enzymatic steps whichleads to the biosynthesis and excretion of cytokines such as TNFα andIL-1. Known inhibitors of p38 kinase have been reviewed by G J Hanson inExpert Opinions on Therapeutic Patents, 1997, 7, 729-733. p38 kinase isknown to exist in isoforms identified as p38α and p38β.

It is known from J. Med. Chem., 1996, 39, 3343-3356, that certainbenzamide derivatives can upregulate the expression of the low densitylipoprotein (LDL) receptor in human hepatocyte cells. The disclosedcompounds includeN-(2-cyclohexylethyl)-3-(4-hydroxybenzamido)-4-methylbenzamide.

It is known from Chemical Abstracts, volume 51, columns 5068 and 5069that certain compounds are useful as intermediates in the synthesis ofcompounds with putative trypanocidal activity. The disclosedintermediates include:

-   3-(4-aminobenzamido)-N-(4-carboxy-3-hydroxyphenyl)-4-methylbenzamide,-   N-(4-carboxy-3-hydroxyphenyl)-4-methyl-3-(4-nitrobenzamido)benzamide,-   3-(4-aminobenzamido)-4-methyl-N-(2-pyridyl)benzamide,-   4-methyl-3-(4-nitrobenzamido)-N-(2-pyridyl)benzamide,-   3-(4-aminobenzamido)-4-methyl-N-(2-thiazolyl)benzamide and-   4-methyl-3-(4-nitrobenzamido)-N-(2-thiazolyl)benzamide.

The following compounds are also known as chemical intermediates:

-   3-benzamido-4-chloro-N-(2-fluoroanilino)benzamide (Chemical    Abstracts, volume 118, abstract 70021),-   3-(2-hydroxy-4-methylbenzamido)-N-4-hydroxyphenyl)-4-methylbenzamide    (U.S. Pat. No. 1,903,899),-   3-(3-hydroxy-2-naphthoylamino)-4-methyl-N-phenylbenzamide (U.S. Pat.    No. 1,909,960)-   and    4-chloro-3-(3-hydroxy-2-naphthoylamino)-2-methyl-N-phenylbenzamide    (Chemical Abstracts, volume 106, abstract 215574).

The compounds disclosed in the present invention are inhibitors of theproduction of cytokines such as TNF, in particular of TNFα, and variousinterleukins, in particular IL-1.

According to one aspect of the present invention there is provided anamide derivative of the Formula I

wherein R³ is (1-6C)alkyl or halogeno;

-   Q is aryl or heteroaryl which optionally bears 1, 2, 3 or 4    substituents selected from hydroxy, halogeno, trifluoromethyl,    cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl,    (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,    (1-3C)alkylenedioxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,    (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,    (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,    N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,    (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,    N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,    N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,    hydroxyl-1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,    amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,    di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,    (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,    N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy,    hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,    carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,    carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,    (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,    halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,    (1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,    carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,    carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,    N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,    N-(1-6C)alkyl-cyano-(1-6C)alkylamino,    N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,    N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    N-(1-6C)alkylamino-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,    N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino,    (1-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino,    carboxy-(2-6C)alkanoylamino,    (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,    carbamoyl-(2-6C)alkanoylamino,    N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,    N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,    amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl,    aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,    aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino,    aroylamino, arylsulphonylamino, N-arylsulphamoyl,    aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl,    heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,    N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,    N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino,    heteroarylsulphonylamino, N-heteroarylsulphamoyl,    heteroaryl-(2-6C)alkanoylamino, heterocyclyl,    heterocyclyl-(1-6C)alkyl, heterocyclyloxy,    heterocyclyl-(1-6C)alkoxy, heterocyclylamino,    N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,    N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino,    heterocyclylcarbonylamino, heterocyclylsulphonylamino,    N-heterocyclylsulphamoyl and heterocyclyl-(2-6C)alkanoylamino,-   and wherein any of the substituents on Q defined hereinbefore which    comprise a CH₂ group which is attached to 2 carbon atoms or a CH₃    group which is attached to a carbon atom may optionally bear on each    said CH₂ or CH₃ group a substituent selected from hydroxy, amino,    (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and    heterocyclyl;-   and wherein any aryl, heteroaryl or heterocyclyl group in a    substituent on Q may optionally bear 1 or 2 substituents selected    from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy,    (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,    N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,    (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,    hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,    amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,    di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl;-   R² is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro,    amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl,    (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino or    di-[(1-6C)alkyl]amino;-   p is 0, 1 or 2;-   q is 0, 1, 2, 3 or 4; and-   R⁴ is aryl, aryl-(1-6C)alkoxy, aryloxy, arylamino,    N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino,    N-(1-6C)alkylaryl-(1-6C)alkylamino, aroylamino, arylsulphonylamino,    N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, cycloalkyl, heteroaryl,    heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,    N-(1-6C)alkylheteroarylamino, heteroaryl-(1-6C)alkylamino,    N-(1-6C)alkylheteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino,    heteroarylsulphonylamino, N-heteroarylsulphamoyl,    heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyloxy,    heterocyclyl-(1-6C)alkoxy, heterocyclylamino,    N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,    N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino,    heterocyclylcarbonylamino, heterocyclylsulphonylamino,    N-heterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoylamino-   and R⁴ optionally bears 1, 2, 3 or 4 substituents selected from    hydroxy, halogeno, tifluoromethyl, cyano, mercapto, nitro, amino,    carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl,    (2-6C)alkynyl, (1-6C)alkoxy, (1-3 C)alkylenedioxy, (1-6C)alkylthio,    (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,    di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,    N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,    (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,    N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,    N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,    hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,    amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,    di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,    (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,    N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy,    hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,    carboxy-(1-6C)alkoxy, 1-6C)alkoxycarbonyl-(1-6C)alkoxy,    carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,    (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,    halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,    (1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,    carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,    carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,    N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,    N-(1-6C)alkyl-cyano-(1-6C)alkylamino,    N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,    N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    N-(1-6C)alklyamino-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,    N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino,    (1-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino,    carboxy-(2-6C)alkanoylamino,    (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,    carbamoyl-(2-6C)alkanoylamino,    N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,    N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,    amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl,    aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,    aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino,    aroylamino, arylsulphonylamino, N-arylsulphamoyl,    aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl,    heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,    N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,    N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino,    heteroarylsulphonylamino, N-heteroarylsulphamoyl,    heteroaryl-(2-6C)alkanoylamino, heterocyclyl,    heterocyclyl-(1-6C)alkyl, heterocyclyloxy,    heterocyclyl-(1-6C)alkoxy, heterocyclylamino,    N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,    N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino,    heterocyclylcarbonylamino, heterocyclylsulphonylamino,    N-heterocyclylsulphamoyl and heterocyclyl-(2-6C)alkanoylamino,-   and wherein any of the substituents on R⁴ defined hereinbefore which    comprise a CH₂ group which is attached to 2 carbon atoms or a CH₃    group which is attached to a carbon atom may optionally bear on each    said CH₂ or CH₃ group a substituent selected from hydroxy, amino,    (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and    heterocyclyl;-   and wherein any aryl, heteroaryl or heterocyclyl group in a    substituent on R⁴ may optionally bear 1 or 2 substituents selected    from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy,    (1-6C)alkoxycabonyl, N-(1-6C)alkylcarbamoyl,    N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,    (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,    hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,    amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,    di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl;-   or a pharmaceutically-acceptable salt or in-vivo-cleavable ester    thereof;    except that the compounds-   N-(2-cyclohexylethyl)-3-(4-hydroxybenzamido)-4-methylbenzamide,-   3-(4-aminobenzamido)-N-4-carboxy-3-hydroxyphenyl)-4-methylbenzamide,-   N-(4-carboxy-3-hydroxyphenyl)-4-methyl-3-(4-nitrobenzamido)benzamide,-   3-(4-aminobenzamido)-4-methyl-N-(2-pyridyl)benzamide,-   4-methyl-3-(4-nitrobenzamido)-N-(2-pyridyl)benzamide,-   3-(4-aminobenzamido)-4-methyl-N-(2-thiazolyl)benzamide,-   4-methyl-3-(4-nitrobenzamido)-N-(2-thiazolyl)benzamide,-   3-benzamido-4-chloro-N-(2-fluoroanilino)benzamide,-   3-(2-hydroxy-4-methylbenzamido)-N-(4-hydroxyphenyl)-4-methylbenzamide,-   3-(3-hydroxy-2-naphthoylamino)-4-methyl-N-phenylbenzamide and-   4-chloro-3-(3-hydroxy-2-naphthoylamino)-2-methyl-N-phenylbenzamide    are excluded.

According to a further aspect of the invention there is provided anamide derivative of the Formula I

-   wherein R³ is (1-6C)alkyl or halogeno;-   Q is aryl or heteroaryl which optionally bears 1, 2, 3 or 4    substituents selected from hydroxy, halogeno, trifluoromethyl,    cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl,    (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,    (1-3C)alkylenedioxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,    (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,    (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,    N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,    (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,    N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,    N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,    hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,    amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,    di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,    (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,    N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy,    hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,    carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,    carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,    (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,    halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,    (1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,    carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,    carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,    N-(1-6C)alkyl-hydroxy-2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,    N-(1-6C)alkyl-cyano-(1-6C)alkylamino,    N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,    N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    N-(1-6C)alklyamino-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,    N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino,    (1-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino,    carboxy-(2-6C)alkanoylamino,    (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,    carbamoyl-(2-6C)alkanoylamino,    N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,    N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,    amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl,    aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,    aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino,    aroylamino, arylsulphonylamino, N-arylsulphamoyl,    aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl,    heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,    N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,    N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino,    heteroarylsulphonylamino, N-heteroarylsulphamoyl,    heteroaryl-(2-6C)alkanoylamino, heterocyclyl,    heterocyclyl-(1-6C)alkyl, heterocyclyloxy,    heterocyclyl-(1-6C)alkoxy, heterocyclylamino,    N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,    N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino,    heterocyclylcarbonylamino, heterocyclylsulphonylamino,    N-heterocyclylsulphamoyl and heterocyclyl-(2-6C)alkanoylamino, and    wherein any aryl, heteroaryl or heterocyclyl group in a substituent    on Q may optionally bear 1 or 2 substituents selected from hydroxy,    halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,    N-(1-6C)alkylcarbamoyl, N,N-4-[(1-6C)alkyl]carbamoyl,    (2-6C)alkanoyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;-   R² is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro,    amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl,    (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino or    di-[(1-6C)alkyl]amino;-   p is 0, 1 or 2;-   q is 0, 1, 2, 3or 4; and-   R⁴ is aryl, aryl-(1-6C)alkoxy, aryloxy, arylamino,    N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino,    N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, arylsulphonylamino,    N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, cycloalkyl, heteroaryl,    heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,    N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,    N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino,    heteroarylsulphonylamino, N-heteroarylsulphamoyl,    heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyloxy,    heterocyclyl-(1-6C)alkoxy, heterocyclylamino,    N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,    N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino,    heterocyclylcarbonylamino, heterocyclylsulphonylamino,    N-heterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoylamino and R⁴    optionally bears 1, 2, 3 or 4 substituents selected from hydroxy,    halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,    carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,    (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylthio,    (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,    di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,    N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,    (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,    N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,    N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,    hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,    amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,    di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,    (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,    N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy,    hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,    carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,    carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,    (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,    halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,    (1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,    carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,    carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,    N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,    N-(1-6C)alkyl-cyano-(1-6C)alkylamino,    N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,    N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,    N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,    N-(1-6C)alklyamino-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,    N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkylamino,    (1-6C)alkoxy-(2-6C)alkanoylamino, cyano-2-6C)alkanoylamino,    carboxy-(2-6C)alkanoylamino,    (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,    carbamoyl-(2-6C)alkanoylamino,    N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,    N,N-di-[(1-,6C)alkyl]carbamoyl-(2-6C)alkanoylamino,    amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl,    aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,    aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino,    aroylamino, arylsulphonylamino, N-arylsulphamoyl,    aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl,    heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,    N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,    N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino,    heteroarylsulphonylamino, N-heteroarylsulphamoyl,    heteroaryl-(2-6C)alkanoylamino, heterocyclyl,    heterocyclyl-(1-6C)alkyl, heterocyclyloxy,    heterocyclyl-(1-6C)alkoxy, heterocyclylamino,    N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,    N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino,    heterocyclylcarbonylamino, heterocyclylsulphonylamino,    N-heterocyclylsulphamoyl and heterocyclyl-(2-6C)alkanoylamino, and    wherein any aryl, heteroaryl or heterocyclyl group in a substituent    on R⁴ may optionally bear 1 or 2 substituents selected from hydroxy,    halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,    N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,    (2-6C)alkanoyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;-   or a pharmaceutically-acceptable salt or in-vivo-cleavable ester    thereof;    except that the compounds:-   N-(2-cyclohexylethyl)-3-(4-hydroxybenzamido)-4-methylbenzamide,-   3-(4-aminobenzamido)-N-4-carboxy-3-hydroxyphenyl)-4-methylbenzamide,-   N-(4-carboxy-3-hydroxyphenyl)-4-methyl-3-(4-nitrobenzamido)benzamide,-   3-(4-aminobenzamido)-4-methyl-N-(2-pyridyl)benzamide,-   4-methyl-3-(4-nitrobenzamido)-N-(2-pyridyl)benzamide,-   3-(4-aminobenzamido)-4-methyl-N-(2-thiazolyl)benzamide,-   4-methyl-3-(4-nitrobenzamido)-N-(2-thiazolyl)benzamide,-   3-benzamido-4-chloro-N-(2-fluoroanilino)benzamide,-   3-(2-hydroxy-4-methylbenzamido)-N-(4-hydroxyphenyl)-4-methylbenzamide,-   3-(3-hydroxy-2-naphthoylamino)-4-methyl-N-phenylbenzamide and-   4-chloro-3-(3-hydroxy-2-naphthoylamino)-2-methyl-N-phenylbenzamide    are excluded.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of inhibiting cytokines, in particular TNF. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against TNF may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for Q or R⁴ or for a substituent on Q or R⁴ when it isaryl or for the aryl group within a substituent on Q or R⁴ is, forexample, phenyl or naphthyl, preferably phenyl.

A suitable value for Q or R⁴ or for a substituent on Q or R⁴ when it isheteroaryl or for the heteroaryl group within a substituent on Q or R⁴is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or10-membered bicyclic ring with up to five ring heteroatoms selected fromoxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,cinnolinyl or naphthyridinyl, preferably furyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl ornaphthyridinyl, more preferably isoxazolyl, pyridyl, benzothiazolyl,quinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl.

A suitable value for R⁴ or for a substituent on Q or R⁴ when it isheterocyclyl or for the heterocyclyl group within a substituent on Q orR⁴ is, for example, a non-aromatic saturated or partially saturated 5 to10 membered monocyclic or bicyclic ring with up to five heteroatomsselected from oxygen, nitrogen and sulphur, for example pyrrolinyl,pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl,homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl or tetrahydropyrimidinyl, preferably pyrrolidin-1-yl,morpholino, piperidino, piperazin-1-yl or homopiperazin-1-yl.

Suitable values for various R³ or R² groups, or for various substituentson Q or R⁴ or on an aryl, heteroaryl or heterocyclyl group in asubstituent on Q or R⁴ include:

-   for halogeno: fluoro, chloro, bromo and iodo;-   for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;-   for (2-6C)alkenyl: vinyl and allyl;-   for (2-6C)alkynyl: ethynyl and 2-propynyl;-   for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;-   for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,    propoxycarbonyl and tert-butoxycarbonyl;-   for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and    N-propylcarbamoyl;-   for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,    N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl;-   for (2-6C)alkanoyl: acetyl and propionyl;-   for (1-6C)alkylamino: methylamino, ethylamino and propylamino;-   for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino and    N-ethyl-N-methylamino;-   for halogeno-(1-6C)alkyl: fluoromethyl, chloromethyl, bromomethyl,    difluoromethyl, dichloromethyl, dibromomethyl, 2-fluoroethyl,    2-chloroethyl and 2-bromoethyl;-   for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl,    1-hydroxyethyl and 3-hydroxypropyl;-   for (1-4C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl,    1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;-   for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and    3-cyanopropyl;-   for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and    3-aminopropyl;-   for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl,    ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl,    2-ethylaminoethyl and 3-methylaminopropyl;-   for di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,    diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and    3-dimethylaminopropyl.

A suitable value for R⁴ when it is cycloalkyl is, for example, anon-aromatic mono- or bicyclic 4- to 10-membered carbon ring such ascyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyland bicyclo[4.4.0]decyl, preferably cyclobutyl, cyclopentyl, cyclohexylor cycloheptyl.

Suitable values for R⁴ and suitable values for a substituent on Q or R⁴include:

-   for aryl-(1-6C)alkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and    3-phenylpropyl;-   for aryl-(1-6C)alkoxy: benzyloxy and 2-phenylethoxy;-   for aryloxy: phenoxy and 2-naphthyloxy;-   for arylamino: anilino;-   for N-(1-6C)alkyl-arylamino: N-methylanilino and N-ethylanilino;-   for aryl-(1-6C)alkylamino: benzylamino, 2-phenethylamino,    2-phenylpropylamino and 3-phenylpropylamino;-   for N-(1-6C)alkyl-aryl-(1-6C)alkylamino: N-benzyl-N-methylamino;-   for aroylamino: benzamido and 2-naphthoylamino; arylsulphonylamino:    benzenesulphonylamido;-   for N-arylsulphamoyl: N-phenylsulphamoyl;-   for aryl-(2-6C)alkanoylamino: phenylacetamido and    3-phenylpropionamido;-   for heteroaryl-(1-6C)alkyl: heteroarylmethyl, 2-heteroarylethyl,    2-heteroarylpropyl and 3-heteroarylpropyl;-   for heteroaryl-(1-6C)alkoxy: heteroarylmethoxy and    2-heteroarylethoxy;-   for N-(1-6C)alkyl-heteroarylamino: N-methylheteroarylamino;-   for heteroaryl-(1-6C)alkylamino: heteroarylmethylamino,    2-heteroarylethylamino and 3-heteroarylpropylamino;-   for N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino:    N-methylheteroarylmethylamino and N-methyl-2-heteroarylethylamino;-   for heteroaryl-(2-6C)alkanoylamino: heteroarylacetamido and    3-heteroarylpropionamido;-   for heterocyclyl-(1-6C)alkyl: heterocyclylmethyl and    2-heterocyclylethyl;-   for heterocyclyl-(1-6C)alkoxy: heterocyclylmethoxy and    2-heterocyclylethoxy;-   for N-(1-6C)alkyl-heterocyclylamino: N-methylheterocyclylamino;-   for heterocyclyl-(1-6C)alkylamino: heterocyclylmethylamino,    2-heterocyclylethylamino and 3-heterocyclylpropylamino;-   for N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino:    N-methylheterocyclylmethylamino and    N-methyl-2-heterocyclylethylamino;-   for heterocyclyl-(2-6C)alkanoylamino: heterocyclylacetamido and    3-heterocyclylpropionamido;-   for (1-3C)alkylenedioxy: methylenedioxy, ethylenedioxy and    propylenedioxy;-   for (1-6C)alkylthio: methylthio, ethylthio and propylthio;-   for (1-6C)alkylsulphinyl: methylsulphinyl, ethylsulphinyl and    propylsulphinyl;-   for (1-6C)alkylsulphonyl: methylsulphonyl, ethylsulphonyl and    propylsulphonyl;-   for (2-6C)alkanoyloxy: acetoxy and propionyloxy;-   for (1-6C)alkanoylamino: formamido, acetamido and propionamido;-   for N-(1-6C)alkylsulphamoyl: N-methylsulphamoyl and    N-ethylsulphamoyl;-   for N,N-di-[(1-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl;-   for (1-6C)alkanesulphonylamino: methanesulphonylamino and    ethanesulphonylamino;-   for N-(1-6C)alkyl-(1-6C)alkanesulphonylamino:    N-methylmethanesulphonylamino and N-methylethanesulphonylamino;-   for carboxy-(1-6C)alkyl: carboxymethyl, 1-carboxyethyl,    2-carboxyethyl, 3-carboxypropyl and 4-carboxybutyl;-   for (1-6C)alkoxycarbonyl-(1-6C)alkyl: methoxycarbonylmethyl,    ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,    1-methoxycarbonylethyl, 1-ethoxycarbonylethyl,    2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,    3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl;-   for carbamoyl-(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl,    2-carbamoylethyl and 3-carbamoylpropyl;-   for N-(1-6C)alkylcarbamoyl-(1-6C)alkyl: N-methylcarbamoylmethyl,    N-ethylcarbamoylmethyl, N-propylcarbarnoylmethyl,    1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,    2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and    3-(N-methylcarbamoyl)propyl;-   for N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl:    N,N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoylmethyl,    N,N-diethylcarbainoylmethyl, 1-(N,N-dimethylcarbamoyl)ethyl,    1-(N,N-diethylcarbamoyl)ethyl, 2-(N,N-dimethylcarbamoyl)ethyl,    2-(N,N-diethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl and    4(N,N-dimethylcarbamoyl)butyl;-   for halogeno-(2-6C)alkoxy: 2-chloroethoxy, 2-bromoethoxy and    3-chloropropoxy;-   for hydroxy-(2-6C)alkoxy: 2-hydroxyethoxy, 2-hydroxy-1-methylethoxy,    3-hydroxypropoxy, 2-hydroxypropoxy and 4hydroxybutoxy;-   for (1-6C)alkoxy-(2-6C)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy,    3-methoxypropoxy, 2-methoxy-1-methylethoxy and 4-ethoxybutoxy;-   for cyano-(1-6C)alkoxy: cyanomethoxy, 2-cyanoethoxy and    3-cyanopropoxy;-   for carboxy-(1-6C)alkoxy: carboxymethoxy, 1-carboxyethoxy,    2-carboxyethoxy and 3-carboxypropoxy;-   for (1-6C)alkoxycarbonyl-(1-6C)alkoxy: methoxycarbonylmethoxy,    ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy,    2-methoxycarbonylethoxy and 3-ethoxycarbonylpropoxy;-   for carbamoyl-(1-6C)alkoxy: carbamoylmethoxy and 2-carbamoylethoxy;-   for N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy: N-methylcarbamoylmethoxy,    2-(N-ethylcarbamoyl)ethoxy and 3-(N-methylcarbamoyl)propoxy;-   for (N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy:    N,N-dimethylcarbamoylmethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy and    3-(N,N-diethylcarbamoyl)propoxy;-   for amino-(2-6C)alkoxy: 2-aminoethoxy, 2-amino-1-methylethoxy,    3-aminopropoxy, 2-amino-2-methylpropoxy and 4-aminobutoxy;-   for (1-6C)alkylamino-(2-6C)alkoxy: 2-methylaminoethoxy,    2-methylamino-1-methylethoxy and 3-ethylaminopropoxy;-   for di-[(1-6C)alkyl]amino-(2-6C)alkoxy: 2-dimethylaminoethoxy,    2-diethylaminoethoxy, 2-dimethylaminopropoxy,    2-dimethylamino-2-methylpropoxy, 3-dimethylaminopropoxy and    4-dimethylaminobutoxy;-   for halogeno-(2-6C)alkylamino: 2-fluoroethylamino,    2-chloroethylamino, 2-bromoethylamino, 3-fluoropropylamino and    3-chloropropylamino;-   for hydroxy-(2-6C)alkylamino: 2-hydroxyethylamino,    3-hydroxypropylamino, 2-hydroxy-2-methylpropylamino and    4-hydroxybutylamino;-   for (1-6C)alkoxy-(2-6C)alkylamino: 2-methoxyethylamino,    2-ethoxyethylamino, 3-methoxypropylamino and 3-ethoxypropylamino;-   for cyano-(1-6C)alkylamino: cyanomethylamino, 2-cyanoethylamino and    3-cyanopropylamino;-   for carboxy-(1-6C)alkylamino: carboxymethylamino,    1-carboxyethylamino, 2-carboxyethylamino and 3-carboxypropylamino;-   for (1-6C)alkoxycarbonyl-(1-6C)alkylamino:    methoxycarbonylmethylamino, 2-(ethoxycarbonyl)ethylamino and    3-(tert-butoxycarbonyl)propylamino;-   for carbamoyl-(1-6C)alkylamino: carbamoylmethylamino and    2-carbamoylethylamino;-   for N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino:    N-methylcarbamoylmethylamino, N-ethylcarbamoylmethylamino and    2-(N-methylcarbamoyl)ethylamino;-   for N N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino:    N,N-dimethylcarbamoyl-methylamino, N,N-diethylcarbamoylmethylamino    and 2-(N,N-dimethylcarbamoyl)ethylamino;-   for amino-(2-6C)alkylamino: 2-aminoethylamino, 3-aminopropylamino,    2-amino-2-methylpropylamino and 4-aminobutylamino;-   for (1-6C)alkylamino-(2-6C)alkylamino: 2-methylaminoethylamino,    2-ethylaminoethylamino, 2-propylaminoethylamino,    3-methylaminopropylamino, 3-ethylaminopropylamino,    2-methylamino-2-methylpropylamino and 4-methylaminobutylamino;-   for di-[(1-6C)alkyl]amino-(2-6C)alkylamino:    2-dimethylaminoethylamino, 2-(N-ethyl-N-methylamino)ethylamino,    2-diethylaminoethylamino, 2-dipropylaminoethylamino,    3-dimethylaminopropylamino, 3-diethylaminopropylamino,    2-dimethylamino-2-methylpropylamino and 4-dimethylaminobutylamino;-   for N-(1-6C)alkyl-halogeno-(2-6C)alkylamino:    N-(2-chloroethyl)-N-methylamino, N-(2-bromoethyl)-N-methylamino and    N-(2-bromoethyl)-N-ethylamino;-   for N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino:    N-(2-hydroxyethyl)N-methylamino, N-(3-hydroxypropyl)-N-methylamino    and N-ethyl-N-(2-hydroxyethyl)amino;-   for N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino:    N-methyl-N-(2-methoxyethyl)amino, N-methyl-N-(3-methoxypropyl)amino    and N-ethyl-N-(2-methoxyethyl)amino;-   for N-(1-6C)alkyl-cyano-(1-6C)alkylamino:    N-(cyanomethyl)-N-methylamino;-   for N-(1-6C)alkyl-carboxy-(1-6C)alkylamino:    N-carboxymethyl-N-methylamino and N-(2-carboxyethyl)-N-methylamino;-   for N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino:    N-methoxycarbonylmethyl-N-methylamino,    N-(2-ethoxycarbonylethyl)-N-ethylamino and    N-(2-tert-butoxycarbonylethyl)-N-methylamino;-   for N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino:    N-carbamoylmethyl-N-methylamino and    N-(2-carbamoylethyl)-N-methylamino;-   for N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino:    N-(N-methylcarbamoylmethyl)-N-methylamino,    N-(N-ethylcarbamoylmethyl)-N-methylamino and    N-[2-N-methylcarbamoyl)ethyl]-N-methylamino;-   for N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino:    N,N-dimethylcarbamoylmethyl)-N-methylamino and    N-[2-(N,N-dimethylcarbamoyl)ethyl]-N-methylamino;-   for N-(1-6C)akyl-amino-(2-6C)alkylamino:    N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino and    N-(4-aminobutyl)-N-methylamino;-   for N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino:    N-(2-methylaminoethyl)-N-methylamino,    N-(2-ethylaminoethyl)-N-methylamino,    N-(3-methylaminopropyl)-N-methylamino,    N-(3-ethylaminopropyl)-N-ethylamino and    N-(4-methylaminobutyl)-N-methylamino;-   for N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino:    N-(2-dimethylaminoethyl)-N-methylamino,    N-(2-diethylaminoethyl)-N-methylamino,    N-(3-dimethylaminopropyl)-N-methylamino and    N-(4-dimethylaminobutyl)-N-methylamino;-   for halogeno-(2-6C)alkanoylamino: 2-chloroacetamido and    3-chloropropionamido;-   for hydroxy-(2-6C)alkanoylamino: 2-hydroxyacetamido and    3-hydroxypropionamido;-   for (1-6C)alkoxy-(2-6C)alkanoylamino: 2-methoxyacetamido and    3-methoxypropionamido;-   for cyano-(2-6C)alkanoylamino: 2-cyanoacetamido and    3-cyanopropionamido;-   for carboxy-(2-6C)alkanoylamino: 2-carboxyacetamido and    3-carboxypropionamido;-   for (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino:    2-methoxycarbonylacetamido, 2-(tert-butoxycarbonyl)acetamido and    3-methoxycarbonylpropionamido;-   for carbamoyl-(2-6C)alkanoylamino: 2-carbamoylacetamido,    3-carbamoylpropionamido and 4-carbamoylbutyramido;-   for N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino:    2-(N-methylcarbamoyl)acetamido and 3-(N-ethylcarbamoyl)propionamido;-   for N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino:    2-(N,N-dimethylcarbamoyl)acetamido,    2-(N,N-diethylcarbamoyl)acetamido and    3-(N,N-dimethylcarbamoyl)propionamido;-   for amino-(2-6C)alkanoylamino: 2-aminoacetamido, 2-aminopropionamido    and 3-aminopropionamido;-   for (1-6C)alkylamino-(2-6C)alkanoylamino: 2-methylaminoacetamido,    2-ethylaminoacetamido, 2-methylaminopropionamido and    3-methylaminopropionamido;-   for di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino:    2-dimethylaminoacetamido, 2-diethylaminoacetamido,    2-dimethylaminopropionamido and 3-dimethylaminopropionamido.

When, as defined hereinbefore, any of the substituents on Q or R⁴ whichcomprise a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₃ group a substituent selected from hydroxy, amino, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, suitablesubstituents so formed include, for example, substitutedheterocyclyl-(1-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxyand 2-hydroxy-3-morpholinopropoxy, substituted amino-(2-6C)alkoxy groupssuch as 3-amino-2-hydroxypropoxy, substituted(1-6C)alkylamino-(2-6C)alkoxy groups such as2-hydroxy-3-methylaminopropoxy, substituteddi-[(1-6C)alkyl]amino-(2-6C)alkoxy groups such as3-dimethylamino-2-hydroxypropoxy,3-[N-(3-dimethylaminopropyl)-N-methylamino]propoxy and3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropoxy,substituted heterocyclyl-(1-6C)alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,substituted amino-(2-6C)alkylamino groups such as3-amino-2-hydroxypropylamino, substituted(1-6C)alkylamino-(2-6C)alkylamino groups such as2-hydroxy-3-methylaminopropylamino, substituteddi-[(1-6C)alkyl]amino-(2-6C)alkylamino groups such as3-dimethylamino-2-hydroxypropylamino,3-[N-(3-dimethylaminopropyl)-N-methylamino]propylamino and3-[N-(3-dimethylaminopropyl)N-methylamino]-2-hydroxypropylamino,substituted (1-6C)alkylamino-(1-6C)alkyl groups such as2-methoxyethylaminomethyl, 3-dimethylaminopropylaminomethyl,2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and3-morpholinopropylaminomethyl, and substituteddi-[(1-6C)alkyl]amino-(1-6C)alkyl groups such asN-(3-dimethylaminopropyl)-N-methylaminomethyl.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula Iwhich is sufficiently basic, for example an acid-addition salt with aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,trifluoroacetic, citric or maleic acid; or, for example a salt of acompound of the Formula I which is sufficiently acidic, for example analkali or alkaline earth metal salt such as a calcium or magnesium salt,or an ammonium salt, or a salt with an organic base such as methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Various forms of prodrugs are known in the art. For examples of suchprodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113-191 30 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   e) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984).

Examples of such pro-drugs may be used to form in-vivo-cleavable estersof a compound of the Formula I. An in-vivo-cleavable ester of a compoundof the Formula I containing a carboxy group is, for example, apharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for carboxy include(1-6C)alkoxymethyl esters, for example methoxymethyl;(1-6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl;phthalidyl esters;

-   (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters, for example    1-cyclohexylcarbonyloxyethyl;-   1,3-dioxolan-2-ylmethyl esters, for example    5-methyl-1,3-dioxolan-2-ylmethyl; and (1-6C)alkoxycarbonyloxyethyl    esters, for example 1-methoxycarbonyloxyethyl; and may be formed at    any carboxy group in the compounds of this invention.

Particular novel compounds of the invention include, for example, amidederivatives of the Formula I, or pharmaceutically-acceptable saltsthereof, wherein:

-   (a) R³ is (1-6C)alkyl such as methyl, ethyl, propyl and isopropyl,    preferably methyl and ethyl, more preferably methyl; and Q, R², R⁴,    p and q have any of the meanings defined hereinbefore or in this    section relating to particular novel compounds of the invention;-   (b) R³ is halogeno such as fluoro, bromo and chloro, preferably    chloro and bromo, more preferably chloro; and Q, R², R⁴, p and q    have any of the meanings defined hereinbefore or in this section    relating to particular novel compounds of the invention;-   (c) Q is phenyl which bears 1, 2 or 3 substituents selected from    hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy,    (1-6C)alkyl, (1-6C)alkoxy, (1-3 C)alkylenedioxy, (1-6C)alkylamino,    di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, (2-6C)akanoyl,    halogeno-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl,    (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,    halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy,    (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy,    (1-6C)alkoxycarbonyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,    (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,    pyridyl-(1-6C)alkyl, imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy,    imidazolyl-(1-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl,    piperazinyl, 4-(1-6C)alkylpiperazinyl, 4-(2-6C)alkanoylpiperazinyl,    pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl,    morpholinyl-(1-6C)alkyl, piperazinyl-(1-6C)alkyl,    4-(1-6C)alkylpiperazinyl-(1-6C)alkyl,    4-(2-6C)alkanoylpiperazinyl-(1-6C)alkyl, pyrrolidinyloxy,    piperidinyloxy, 1-(1-6C)alkylpiperidinyloxy,    pyrrolidinyl-(2-6C)alkoxy, piperidinyl-(2-6C)alkoxy,    morpholinyl-(2-6C)alkoxy, piperazinyl-(2-6C)alkoxy,    4-(1-6C)alkylpiperazinyl-(2-6C)alkoxy and    4-(2-6C)alkanoylpiperazinyl-(2-6C)alkoxy; and R², R³, R⁴, p and q    have any of the meanings defined hereinbefore or in this section    relating to particular novel compounds of the invention;-   (d) Q is a heteroaromatic 5- or 6-membered monocyclic ring or a 9-    or 10-membered bicyclic ring with up to five ring heteroatoms    selected from oxygen, nitrogen and sulphur which optionally bears 1    or 2 substituents selected from hydroxy, halogeno, trifluoromethyl,    cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy,    (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl;    and R², R³, R⁴, p and q have any of the meanings defined    hereinbefore or in this section relating to particular novel    compounds of the invention;-   (e) Q is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl,    pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl,    benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,    benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or    naphthyridinyl which optionally bears 1 or 2 substituents selected    from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino,    carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino,    di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; and R², R³, R⁴, p    and q have any of the meanings defined hereinbefore or in this    section relating to particular novel compounds of the invention;-   (f) Q is 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-oxazolyl, 3-,    4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3- or 4-pyrazolyl, 2-,    4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 3-    or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-, 3-, 5-    or 6-benzofuranyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or    6-benzothienyl, 2-, 5- or 6-benzoxazolyl, 2-, 5- or    6-benzimidazolyl, 2-, 5- or 6-benzothiazolyl, 3-, 5- or 6-indazolyl,    5-benzofurazanyl, 2-, 3-, 6- or 7-quinolyl, 3-, 6- or 7-isoquinolyl,    2-, 6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl, or    1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl which optionally    bears 1 or 2 substituents selected from hydroxy, halogeno,    trifluoromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl,    (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and    (1-6C)alkoxycarbonyl; and R², R³, R⁴, p and q have any of the    meanings defined hereinbefore or in this section relating to    particular novel compounds of the invention;-   (g) q is 0, and R⁴ is phenyl which bears 1, 2 or 3 substituents    selected from hydroxy, halogeno, trifluoromethyl, cyano, amino,    (1-6C)alkyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino,    di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, halogeno-(1-6C)alkyl,    (1-6C)alkoxy-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,    di-[(1-6C)alkyl]amino-(1-6C)alkyl, halogeno-(2-6C)alkoxy,    hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(2-6C)alkoxy,    carboxy-(2-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,    amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy,    di-[(1-6)alkyl]amino-(2-6C)alkoxy, halogeno-(2-6C)alkylamino,    hydroxy-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino,    amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,    di-[(1-6C)alkyl]amino-(2-6C)alkylamino,    N-(1-6C)alkyl-halogeno-(2-6C)alkylamino,    N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,    N-(1-6C)alklyamino-(2-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,    N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, phenyl,    benzyl, benzyloxy, pyridyl, imidazolyl, pyridyl-(1-6C)alkyl,    imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy,    imidazolyl-(1-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl,    piperazinyl, 4-(1-6C)alkylpiperazinyl, 4-(2-6C)alkanoylpiperazinyl,    pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl,    morpholinyl-(1-6C)alkyl, piperazinyl-(1-6C)alkyl,    4-(1-6C)alkylpiperazinyl-(1-6C)alkyl,    4-(2-6C)alkanoylpiperazinyl-(1-6C)alkyl, pyrrolidinyloxy,    piperidinyloxy, 1-(1-6C)alkylpiperidinyloxy,    pyrrolidinyl-(2-6C)alkoxy, piperidinyl-(2-6C)alkoxy,    morpholinyl-(2-6C)alkoxy, piperazinyl-(2-6C)alkoxy,    4-(1-6C)alkylpiperazinyl-(2-6C)alkoxy and    4(2-6C)alkanoylpiperazinyl-(2-6C)alkoxy; and R², R³, R⁴, p and q    have any of the meanings defined hereinbefore or in this section    relating to particular novel compounds of the invention;-   (h) p is 0; and Q, R³, R⁴ and q have any of the meanings defined    hereinbefore or in this section relating to particular novel    compounds of the invention;-   (i) q is 0, and R⁴ is furyl, thienyl, oxazolyl, isoxazolyl,    imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl,    pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl,    benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,    indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl,    quinoxalinyl or naphthyridinyl which optionally bears 1 or 2    substituents selected from hydroxy, halogeno, trifluoromethyl,    cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy,    (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl;    and Q, R², R³ and p have any of the meanings defined hereinbefore or    in this section relating to particular novel compounds of the    invention;-   (j) q is 0, and R⁴ is 2- or 3-furyl, 2- or 3-thienyl, 2- , 4- or    5-oxazolyl, 3- , 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3- or    4-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3-    or 4-pyridyl, 3- or 4-pyridazinyl, 2- , 4- or 5-pyrimidinyl,    2-pyrazinyl, 2-, 3-, 5- or 6-benzofuranyl, 2-, 3-, 5- or 6-indolyl,    2-, 3-, 5- or 6-benzothienyl, 2-, 5- or 6-benzoxazolyl, 2-, 5- or    6-benzimidazolyl, 2-, 5- or 6-benzothiazolyl, 3-, 5- or 6-indazolyl,    5-benzofurazanyl, 2-, 3-, 6- or 7-quinolyl, 3-, 6- or 7-isoquinolyl,    2-, 6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl, or    1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl which optionally    bears 1 or 2 substituents selected from hydroxy, halogeno,    trifluoromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl,    (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and    (1-6C)alkoxycarbonyl; and Q, R², R³ and p have any of the meanings    defined hereinbefore or in this section relating to particular novel    compounds of the invention;-   (k) q is 0, and R⁴ is 4- or 5-oxazolyl, 4- or 5-isoxazolyl, 4- or    5-thiazolyl, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 5- or    6-benzofuranyl, 5- or 6-benzothienyl, 5- or 6-benzothiazolyl, 2-,    3-, 6- or 7-quinolyl, 2-, 6- or 7-quinazolinyl, 2-, 6- or    7-quinoxalinyl, 1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl which    optionally bears 1, 2 or 3 substituents selected from hydroxy,    fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, methoxy and    ethoxy; and Q, R², R³ and p have any of the meanings defined    hereinbefore or in this section relating to particular novel    compounds of the invention;-   (l) q is 1, 2, 3 or 4, and R⁴ is cycloalkyl; and Q, R², R³ and p    have any of the meanings defined hereinbefore or in this section    relating to particular novel compounds of the invention; and-   (m) q is 0 and R⁴ is phenyl which is optionally substituted as    defined hereinbefore; and Q, R², R³ and p have any of the meanings    defined hereinbefore or in this section relating to particular novel    compounds of the invention.

In a further aspect of the present invention there is provided a groupof novel compounds of the Formula I wherein Q is substituted by a basicsubstituent selected from the substituents for Q defined hereinbeforeand R⁴ is a phenyl or heteroaryl group as defined hereinbefore whichalso bears a basic substituent selected from the substituents for R⁴defined hereinbefore. This group of compounds possesses improved TNFαinhibitory potency in one or both of the PBMC and Human Whole Blood(HWB) tests described hereinafter.

Suitable basic substituents include, for example, amine derivatives suchas amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(2-6C)alkoxy,di-[(1-6C)alkyl]amino-(2-6C)alkylamino, a heteroaryl group such as anitrogen-containing heteroaryl group, for example imidazolyl and pyridyland a heterocyclyl group such as a nitrogen-containing heterocyclylgroup, for example morpholinyl or piperidinyl.

A preferred compound of the invention is an amide derivative of theFormula I wherein R³ is methyl, ethyl, chloro or bromo;

-   Q is phenyl which bears 1, 2 or 3 substituents selected from    hydroxy, fluoro, chloro, trifluoromethyl, cyano, carboxy, methyl,    ethyl, propyl, methoxy, ethoxy, methylenedioxy, methoxycarbonyl,    ethoxycarbonyl, tert-butoxycarbonyl, acetyl, propionyl,    chloromethyl, methoxymethyl, methylaminomethyl, ethylaminomethyl,    dimethylaminomethyl, diethylaminomethyl, 2-chloroethoxy,    3-chloropropoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,    2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, cyanomethoxy,    carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy,    tert-butoxycarbonylmethoxy, 2-aminoethoxy, 3-aminopropoxy,    2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,    3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,    3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridylmethoxy,    2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy, pyrrolidin-1-yl,    piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl,    4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,    morpholinomethyl, piperazin-1-ylmethyl,    4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl,    piperidin-4-yloxy, 1-methylpiperidin-4-yloxy,    2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,    2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy,    3-morpholinopropoxy, 2-piperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,    3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy    and 3-(4-acetylpiperazin-1-yl)propoxy,-   or Q is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl,    isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,    benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl,    benzothiazolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl,    quinoxalinyl or naphthyridinyl which optionally bears 1 or 2    substituents selected from hydroxy, fluoro, 5 chloro,    trifluoromethyl, cyano, methyl, ethyl, methoxy and ethoxy;-   p is 0;-   q is 0; and-   R⁴ is phenyl which bears 1 or 2 substituents selected from hydroxy,    fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl,    methoxy, ethoxy, methylenedioxy, methylamino, ethylamino,    dimethylamino, diethylamino, acetyl, propionyl, chloromethyl,    methoxymethyl, 2-methoxyethyl, methylaminomethyl, ethylaminomethyl,    dimethylaminomethyl, diethylaminomethyl, 2-chloroethoxy,    3-chloropropoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,    2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, cyanomethoxy,    carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy,    tert-butoxycarbonylmethoxy, 2-aminoethoxy, 3-aminopropoxy,    2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,    3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,    3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-chloroethylamino,    2-hydroxyethylamino, 2-methoxyethylamino, 2-ethoxyethylamino,    2-aminoethylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,    2-dimethylaminoethylamino, 2-diethylaminoethylamino,    N-(2-chloroethyl)-N-methylamino, N-(2-hydroxyethyl)-N-methylamino,    N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-methylamino,    N-(2-aminoethyl)-N-methylamino,    N-(2-methylaminoethyl)-N-methylamino,    N-(2-dimethylaminoethyl)-N-methylamino,    N-(3-aminopropyl)-N-methylamino,    N-(3-methylaminopropyl)-N-methylamino, N-(3-ethylaminopropyl)    N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino,    N-(3-diethylaminopropyl)-N-methylamino, phenyl, benzyl, benzyloxy,    2-pyridylmethoxy, 2imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy,    pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,    4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl,    pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,    piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,    4-acetylpiperazin-1-ylmethyl, piperidin-4-yloxy,    1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,    3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,    2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,    3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy    and 3-(4-acetylpiperazin-1-yl)propoxy;-   or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula I

-   wherein R³ is methyl or chloro;-   Q is phenyl which bears 1, 2 or 3 substituents selected from    hydroxy, fluoro, chloro, cyano, o carboxy, methyl, ethyl, propyl,    methoxy, ethoxy, methylenedioxy, methoxycarbonyl, ethoxycarbonyl,    tert-butoxycarbonyl, acetyl, propionyl, chloromethyl,    dimethylaminomethyl, diethylaminomethyl, 2-methoxyethoxy,    2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy,    methoxycarbonylmethoxy, ethoxycarbonylmethoxy,    tert-butoxycarbonylmethoxy, 2-dimethylaminoethoxy,    2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,    2-pyridylmethoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy,    pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,    4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl,    pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,    piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,    4-acetylpiperazin-1-ylmethyl, 2-(pyrrolidin-1-yl)ethoxy,    3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,    2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,    3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy    and 3-(4-acetylpiperazin-1-yl)propoxy, or Q is 2-furyl, 2-thienyl,    2-oxazolyl, 3-isoxazolyl, 2-imidazolyl, 2-thiazolyl, 3-isothiazolyl,    2-, 3- or 4-pyridyl, 3-pyridazinyl, 2- or 4-pyrimidinyl,    2-pyrazinyl, 5- or 6-benzofuranyl, 5- or 6-indolyl, 5- or    6-benzothienyl, 5- or 6-benzoxazolyl, 5- or 6-benzimidazolyl, 5- or    6-benzothiazolyl, 5- or 6-indazolyl, 2-, 6- or 7-quinolyl, 6- or    7-isoquinolyl, 2-, 6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl or    1,8-naphthyridin-3-yl which optionally bears 1 or 2 substituents    selected from hydroxy, chloro, methyl and ethyl;-   p is 0;-   q is 0; and-   R⁴ is phenyl which bears 1 or 2 substituents selected from hydroxy,    fluoro, chloro, cyano, amino, methyl, methoxy, methylamino,    dimethylamino, 2-chloroethoxy, 3-chloropropoxy, 2-hydroxyethoxy,    3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, carboxymethoxy,    methoxycarbonylmethoxy, ethoxycarbonylmethoxy,    tert-butoxycarbonylmethoxy, 2-dimethylaminoethoxy,    2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,    2-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,    piperazin-1-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl,    pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,    piperazin-I -ylmethyl, 4-methylpiperazin-1-ylmethyl,    4-acetylpiperazin-1-ylmethyl, 2-(pyrrolidin-1-yl)ethoxy,    3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,    2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,    3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-I -yl)ethoxy    and 3-(4-acetylpiperazin-1-yl)propoxy;-   or a pharmaceutically-acceptable salt thereof

A further preferred compound of the invention is an amide derivative ofthe Formula I

-   wherein R³ is methyl or chloro;-   Q is phenyl which bears 1, 2 or 3 substituents selected from    hydroxy, fluoro, chloro, cyano, carboxy, methyl, ethyl, propyl,    methoxy, ethoxy, methylenedioxy, methoxycarbonyl, ethoxycarbonyl,    tert-butoxycarbonyl, acetyl, propionyl, chloromethyl,    dimethylaminomethyl, diethylaminomethyl, 2-methoxyethoxy,    2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy,    methoxycarbonylmethoxy, ethoxycarbonylmethoxy,    tert-butoxycarbonylmethoxy, 2-dimethylaminoethoxy,    2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,    2-pyridylmethoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy,    pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,    4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl,    pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,    piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,    4-acetylpiperazin-1-ylmethyl, 2-(pyrrolidin-1-yl)ethoxy,    3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,    2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,    3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy    and 3-(4-acetylpiperazin-1-yl)propoxy;-   p is 0;-   q is 1 or 2; and-   R⁴ is cyclobutyl, cyclopentyl or cyclohexyl;-   or a pharmaceutically-acceptable salt thereof.

A more preferred compound of the invention is an amide derivative of theFormula I

-   wherein R³ is methyl or chloro;-   Q is phenyl which bears 1, 2 or 3 substituents selected from    hydroxy, cyano, carboxy, methyl, ethyl, propyl, methoxy, ethoxy,    acetyl and 2-methoxyethoxy;-   p is 0;-   q is 0; and-   R⁴ is phenyl which bears 1 or 2 substituents selected from chloro,    cyano and dimethylamino;-   or a pharmaceutically-acceptable salt thereof.

A further more preferred compound of the invention is an amidederivative of the Formula I

-   wherein R³ is methyl or chloro;-   Q is 3-isoxazolyl, 3-pyridyl or 6-quinolyl which optionally bears a    substituent selected from chloro and methyl;-   p is 0;-   q is 0; and-   R⁴ is phenyl which bears a dimethylamino substituent;-   or a pharmaceutically-acceptable salt thereof

A further more preferred compound of this aspect of the invention is anamide derivative of the Formula I

-   wherein R³ is methyl or chloro;-   Q is phenyl which bears a substituent selected from    dimethylaminomethyl, diethylaminomethyl,    N-butyl-N-methylaminomethyl, 2-methylaminoethoxy,    2-diethylaminoethoxy, 2-diisopropylaminoethoxy,    3-dimethylaminopropoxy, 3-diethylaminopropoxy,    3-diisopropylaminopropoxy, pyrrolidin-1-ylmethyl,    3-hydroxypyrrolidin-1-ylmethyl, morpholinomethyl, piperidinomethyl,    homopiperidinomethyl, piperazin-1-ylmethyl,    homopiperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,    4-methylhomopiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,    4-ethylhomopiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,    4-(2-hydroxyethyl)piperazin-1-ylmethyl, 2-pyridylmethoxy,    pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-3-yloxy,    1-methylpiperidin-3-yloxy, homopiperidin-3-yloxy,    1-methylhomopiperidin-3-yloxy, piperidin-4-yloxy,    1-methylpiperidin-4-yloxy, homopiperidin-4-yloxy,    1-methylhomopiperidin-4-yloxy, pyrrolidin-3-ylmethoxy,    1-methylpyrrolidin-3-ylmethoxy, piperidin-3-ylmethoxy,    1-methylpiperidin-3-ylmethoxy, homopiperidin-3-ylmethoxy,    1-methylhomopiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,    1-methylpiperidin-4-ylmethoxy, homopiperidin-4-ylmethoxy,    1-methylhomopiperidin-4-ylmethoxy, 2-(pyrrolidin-1-yl)ethoxy,    3-(pyrrolidin-1-yl)propoxy, 2-(N-methylpyrrolidin-2-yl)ethoxy,    3-(N-methylpyrrolidin-2-yl)propoxy, 2-piperidinoethoxy,    3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,    2-piperazin-1-ylethoxy, 2-homopiperazin-1-ylethoxy,    3-piperazin-1-ylpropoxy, 3-homopiperazin-1-ylpropoxy,    2-(4-methylpiperazin-1-yl)ethoxy,    2-(4-methylhomopiperazin-1-yl)ethoxy,    3-(4-methylpiperazin-1-yl)propoxy,    3-(4-methylhomopiperazin-1-yl)propoxy,    2-(4-acetylpiperazin-1-yl)ethoxy, 3-(4-acetylpiperazin-1-yl)propoxy,    2-methoxyethylaminomethyl, 3-methoxypropylaminomethyl,    2-aminoethylaminomethyl, 3-aminopropylaminomethyl,    3-dimethylamino-2,2-dimethylpropylaminomethyl,    2-methylaminoethylaminomethyl, 3-methylaminopropylaminomethyl,    2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl,    N-(2-methylaminoethyl)-N-methylaminomethyl,    N-(3-methylaminopropyl)-N-methylaminomethyl,    N-(2-dimethylaminoethyl)-N-methylaminomethyl,    N-(3-dimethylaminopropyl)-N-methylaminomethyl and    3-morpholinopropylaminomethyl, and Q is optionally substituted with    a further substituent selected from methyl and methoxy;-   p is 0;-   q is 0; and-   R⁴ is phenyl which is substituted at the 3-position with a    substituent selected from dimethylamino, diethylamino,    pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,    homopiperazin-1-yl, 4-methylpiperazin-1-yl and    4-methylhomopiperazin-1-yl and R⁴ is optionally substituted with a    further substituent selected from fluoro, chloro, cyano, methyl and    trifluoromethyl;-   or a pharmaceutically-acceptable salt thereof

A further more preferred compound of this aspect of the invention is anamide derivative of the Formula I

-   wherein R³ is methyl or chloro;-   Q is 3-pyridyl or 4-pyridyl which bears a substituent selected from    2-aminoethylamino, 3-aminopropylamino, 2-amino-2-methylpropylamino,    4-aminobutylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,    3-methylaminopropylamino, 4-methylaminobutylamino,    2-dimethylaminoethylamino, 2-diethylaminoethylamino,    3-dimethylaminopropylamino, 4-dimethylaminobutylamino,    N-(2-methylaminoethyl)-N-methylamino,    N-(3-methylaminopropyl)-N-methylamino,    N-(4-methylaminobutyl)-N-methylamino,    N-(2-dimethylaminoethyl)-N-methylamino,    N-(3-dimethylaminopropyl)-N-methylamino,    N-(4-dimethylaminobutyl)-N-methylamino, pyrrolidin-1-yl,    3-hydroxypyrrolidin-1-yl, morpholino, piperidino, homopiperidino,    piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl,    4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,    4-methylhomopiperazin-1-yl, 3-morpholinopropylamino or    2-(1-methylpyrrolidin-2-yl)ethylamino;-   p is 0;-   q is 0; and-   R⁴ is phenyl which is substituted at the 3-position with a    substituent selected from dimethylamino, diethylamino,    pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,    homopiperazin-1-yl, 4-methylpiperazin-1-yl and    4-methylhomopiperazin-1-yl and R⁴ is optionally substituted with a    further substituent selected from fluoro, chloro, cyano, methyl and    trifluoromethyl;-   or a pharmaceutically-acceptable salt thereof

A particular preferred compound of the invention is, for example:

-   N-(3-dimethylaminophenyl)-4-methyl-3-(4-propylbenzamido)benzamide,-   3-(3,4-dimethoxybenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamide,-   3-(4-butoxybenzamido)-N-(3-dimethylamino-6phenyl)-4-methylbenzamide,-   4-chloro-N-(3-dimethylaminophenyl)-3-(4-propylbenzamido)benzamide,-   3-(4-carboxybenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamide,-   N-(3,4-dichlorobenzyl)-3-(3,4,5-trimethoxybenzamido)-4-methylbenzamide,-   N-(2-cyclohexylethyl)-3-(3,4-dimethoxybenzamido)-4-methylbenzamide,-   N-(3-dimethylaminophenyl)-4-methyl-3-(6-quinolylcarbonylamino)benzamide    or-   4-chloro-N-(3-dimethylaminophenyl)-3-(6-quinolylcarbonylamino)benzamide;-   or a pharmaceutically-acceptable salt thereof.

A further particular preferred compound of the invention is, forexample:

-   4-methyl-N-(3-morpholinophenyl)-3-(3-piperidin-4-yloxy)benzamido)benzamide,-   4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[3-(1-methylhomopiperidin-4-yloxy)benzamido]benzamide,-   3-(2-diisopropylaminoethoxybenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide,-   3-(4-diethylaminomethylbenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide,-   4-methyl-3-[3-(4-methylhomopiperazin-1-ylmethyl)benzamido]-N-3-morpholinophenyl)-benzamide,-   4-methyl-3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-N-(3-morpholinophenyl)-benzamide    and-   3-[6-(2-amino-2-methylpropylamino)pyrid-3-ylcarbonylamino]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide;-   or a pharmaceutically-acceptable salt thereof.

An amide derivative of the Formula I, or a pharmaceutically-acceptablesalt or in-vivo-cleavable ester thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a novel amide derivativeof the Formula I are provided as a further feature of the invention andare illustrated by the following representative process variants inwhich, unless otherwise stated, Q, R², R³, p, q and R⁴ have any of themeanings defined hereinbefore. Necessary starting materials may beobtained by standard procedures of organic chemistry. The preparation ofsuch starting materials is described in conjunction with the followingrepresentative process variants and within the accompanying Examples.Alternatively necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist.

-   (a) A compound of the Formula I, or a pharmaceutically-acceptable    salt or in-vivo-cleavable ester thereof, may be prepared by reacting    a benzoic acid of the Formula II, or a reactive derivative thereof,

with an amine of the Formula IIIH₂N—(CH₂)_(q)—R⁴   IIIunder standard amide bond forming conditions, wherein variable groupsare as defined hereinbefore and wherein any functional group isprotected if necessary, and:

-   -   (i) removing any protecting groups; and    -   (ii) optionally forming a pharmaceutically-acceptable salt or        in-vivo-cleavable ester.

A suitable activated derivative of an acid of the Formula II is, forexample, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate;an active ester, for example an ester formed by the reaction of the acidand a phenol such as pentafluorophenol, an ester such aspentafluorophenyl trifluoroacetate or an alcohol such asN-hydroxybenzotriazole; an acyl azide, for example an azide formed bythe reaction of the acid and an azide such as diphenylphosphoryl azide;an acyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide; or the product of thereaction of the acid and a carbodiimide such asdicyclohexylcarbodiimide.

The reaction is preferably carried out in the presence of a suitablebase such as, for example, an alkali or alkaline earth metal carbonate,alkoxide, hydroxide or hydride, for example sodium carbonate, potassiumcarbonate, sodium ethoxide, potassium butoxide, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride, or anorganometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. Thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example tetrahydrofuran, methylene chloride,1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at atemperature in the range, for example, −78 to 150° C., conveniently ator near ambient temperature.

Typically a carbodiimide coupling reagent is used in the presence of anorganic solvent (preferably an anhydrous polar aprotic organic solvent)at a non-extreme temperature, for example in the region −10 to 40° C.,typically at ambient temperature of about 20° C.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxylower alkyl groups (for example methoxymethyl, ethoxymethyl,isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (forexample acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (forexample 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl loweralkyl groups (for example benzyl, 1-methoxybenzyl, o-nitrobenzyl,1-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups(for example trimethylsilyl and

-   tert-butyldimethylsilyl);-   tri(lower alkyl)silyl lower alkyl groups (for example    trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl    and vinylethyl). Methods particularly appropriate for the removal of    carboxyl protecting groups include for example acid- , base- ,    metal- or enzymically-catalysed hydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzoyloxycarbonyl, R-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl) andaryl lower alkyl (for example benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (forexample benzyl and substituted benzyl, R-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (for exampletert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, R-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl andtert-butyldimethylsilyl); alkylidene (for example methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid- , base- , metal- or enzymically-catalysedhydrolysis for groups such as nitrobenzyloxycarbonyl, hydrogenation forgroups such as benzyl and photolytically for groups such aso-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, byJerry March, published by John Wiley & Sons 1992, for general guidanceon reaction conditions and reagents. The reader is referred toProtective Groups in Organic Synthesis, 2nd Edition, by Green et al.,published by John Wiley & Sons for general guidance on protectinggroups.

The benzoic acid of Formula II may be prepared by the cleavage of thecorresponding ester thereof which, in turn, may be prepared by reactionof an acid of Formula IV, or an activated derivative thereof as definedhereinbefore,

with an aniline of Formula V

wherein R is, for example, lower alkyl or benzyl, under suitable amidebond forming conditions as defined hereinbefore.

Typical conditions include activating the carboxy group of the compoundof Formula IV, for example by treatment with a halo reagent (for exampleoxalyl chloride) to form an acyl halide in an organic solvent at ambienttemperature and then reacting the activated compound with the aniline ofFormula V. Any functional groups are protected and deprotected asnecessary.

-   (b) A compound of the Formula I, or a pharmaceutically-acceptable    salt or in-vivo-cleavable ester thereof, may be prepared by reacting    an acid of the Formula IV, or an activated derivative thereof as    defined hereinbefore,

with an aniline of the Formula VI

under standard amide bond forming conditions as defined hereinbefore,wherein variable groups are as defined hereinbefore and wherein anyfunctional group is protected, if necessary, and:

-   -   (i) removing any protecting groups;    -   (ii) optionally forming a pharmaceutically-acceptable salt or        in-vivo-cleavable ester.

The aniline of Formula VI may be prepared by reduction of thecorresponding nitro compound using convention procedures such as thoseillustrated in the Examples. Typical reaction conditions include the useof ammonium formate in the presence of a catalyst (for examplepalladium-on-carbon) in the presence of an organic solvent (preferably apolar protic solvent), preferably with heating, for example to about 60°C. Any functional groups are protected and deprotected as necessary.

-   (c) A compound of the Formula I wherein a substituent on Q or R⁴ is    (1-6C)alkoxy or substituted (1-6C)alkoxy, (1-6C)alkylthio,    (1-6C)alkylamino, di-[(1-6C)alkyl]amino or substituted    (1-6C)alkylamino or heterocyclyloxy, may be prepared by the    alkylation, conveniently in the presence of a suitable base as    defined hereinbefore, of an amide derivative of the Formula I    wherein a substituent on Q or R⁴ is hydroxy, mercapto or amino as    appropriate.

The reaction is preferably carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or adipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.The reaction is conveniently carried out at a temperature in the range,for example, 10 to 150° C., preferably in the range 20 to 80° C.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of hydroxy to alkoxy or substituted alkoxy, or forthe alkylation of mercapto to alkylthio, or for the alkylation of aminoto alkylamino or substituted alkylamino, or for the alkylation ofhydroxy to heterocyclyloxy, for example an alkyl or substituted alkylhalide, for example a (1-6C)alkyl chloride, bromide or iodide or asubstituted (1-6C)alkyl chloride, bromide or iodide or a heterocyclylchloride, bromide or iodide, in the presence of a suitable base asdefined hereinbefore.

-   (d) A compound of the Formula I wherein a substituent on Q or R⁴ is    (1-6C)alkanoylamino or substituted (2-6C)alkanoylamino may be    prepared by the acylation of a compound of the Formula I wherein a    substituent on Q or R⁴ is amino.

A suitable acylating agent is, for example, any agent known in the artfor the acylation of amino to acyl amino, for example an acyl halide,for example a (1-6C)alkanoyl chloride or bromide, conveniently in thepresence of a suitable base, as defined hereinbefore, an alkanoic acidanhydride or mixed anhydride, for example a (1-6C)alkanoic acidanhydride such as acetic anhydride or the mixed anhydride formed by thereaction of an alkanoic acid and a (1-6C)alkoxycarbonyl halide, forexample a (1-6C)alkoxycarbonyl chloride, in the presence of a suitablebase as defined hereinbefore. In general the acylation is carried out ina suitable inert solvent or diluent as defined hereinbefore and at atemperature, in the range, for example, −30 to 120° C., conveniently ator near ambient temperature.

-   (e) A compound of the Formula I wherein a substituent on Q or R⁴ is    (1-6C)alkanesulphonylamino may be prepared by the reaction of a    compound of the Formula I wherein a substituent on Q or R⁴ is amino    with a (1-6C)alkanesulphonic acid, or an activated derivative    thereof.

A suitable activated derivative of a (1-6C)alkanesulphonic acid is, forexample, an alkanesulphonyl halide, for example an alkanesulphonylchloride formed by the reaction of the sulphonic acid and an inorganicacid chloride, for example thionyl chloride. The reaction is preferablycarried out in the presence of a suitable base as defined hereinbefore,particularly pyridine, and in a suitable inert solvent or diluent asdefined hereinbefore, particularly methylene chloride.

-   (f) A compound of the Formula I wherein a substituent on Q or R⁴ is    carboxy, carboxy-(1-6C)alkyl, carboxy-(1-6C)alkoxy,    carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-carboxy-(1-6C)alkylamino or    carboxy-(2-6C)alkanoylamino may be prepared by the cleavage of a    compound of the Formula I wherein a substituent on Q or R⁴ is    (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl,    (1-6C)alkoxycarbonyl-(1-6C)alkoxy,    (1-6C)alkoxycarbonyl-(1-6C)alkylamino,    N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino or    (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino as appropriate.

The cleavage reaction may conveniently be carried out by any of the manyprocedures known in the art for such a transformation. The reaction maybe carried out, for example, by hydrolysis under acidic or basicconditions. A suitable base is, for example, an alkali metal, alkalineearth metal or ammonium carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide orammonium hydroxide. The reaction is preferably carried out in thepresence of water and a suitable solvent or diluent such as methanol orethanol. The reaction is conveniently carried out at a temperature inthe range 10 to 150° C., preferably at or near ambient temperature.

-   (g) A compound of the Formula I wherein a substituent on Q or R⁴ is    amino-(1-6C)alkyl, heterocyclyl-(1-6C)alkyl,    (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,    substituted (2-6C)alkylamino-(1-6C)alkyl or substituted    N-(1-6C)alkyl-(2-6C)alkylamino-(1-6C)alkyl may be prepared by the    reaction of a compound of the Formula I wherein a substituent on Q    or R⁴ is a group of the formula -(1-6C)alkylene-Z wherein Z is a    displaceable group with an appropriate amine or heterocyclyl    compound.

A suitable displaceable group Z is, for example, a halogeno group suchas fluoro, chloro or bromo, a (1-6C)alkanesulphonyloxy group such asmethanesulphonyloxy or an arylsulphonyloxy group such as4-toluenesulphonyloxy.

The reaction is conveniently carried out in the presence of a suitablebase as defined hereinbefore and in the presence of a suitable inertdiluent or carrier as defined hereinbefore. The reaction is convenientlycarried out at a temperature in the range 10 to 150° C., preferably ator near 50° C.

-   (h) A compound of the Formula I wherein a substituent on Q or R⁴ is    amino, heterocyclyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,    substituted (1-6C)alkylamino, substituted    N-(1-6C)alkyl-(1-6C)alkylamino, substituted (2-6C)alkylamino or    substituted N-(1-6C)alkyl-(2-6C)alkylamino may be prepared by the    reaction of a compound of the Formula I wherein a substituent on Q    or R⁴ is a displaceable group Z as defined hereinbefore with an    appropriate amine or heterocyclyl compound.

The reaction is conveniently carried out in the presence of a suitablebase as defined hereinbefore and in the presence of a suitable inertdiluent or carrier as defined hereinbefore. The reaction is convenientlycarried out at a temperature in the range 25 to 250° C., preferably ator near 150° C.

-   (i) A compound of the Formula I wherein a substituent on Q or R⁴ is    N-(1-6C)alkyl-(1-6C)alkanesulphonylamino may be prepared by the    alkylation, conveniently in the presence of a suitable base as    defined hereinbefore, of an amide derivative of the Formula I    wherein a substituent on Q or R⁴ is (1-6C)alkanesulphonylamino.

The reaction is conveniently carried out in the presence of a suitableinert diluent or carrier as defined hereinbefore and at a temperature inthe range 10 to 150° C., preferably at or near ambient temperature.

-   (j) A compound of the Formula I wherein a substituent on Q or R⁴ is    a hydroxy-heterocyclyl-(1-6C)alkoxy group (such as    2-hydroxy-3-piperidinopropoxy), a    hydroxy-(1-6C)alkylamino-(2-6C)alkoxy group (such as    2-hydroxy-3-methylaminopropoxy) or a    hydroxy-di-[(1-6C)alkyl]amino-(2-6C)alkoxy group (such as    3-dimethylamino-2-hydroxypropoxy or    3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropoxy) may be    prepared by the reaction of a compound of the Formula I wherein a    substituent on Q or R⁴ is a epoxy-substituted (1-6C)alkoxy group    with a heterocyclyl compound or an appropriate amine.

The reaction is conveniently carried out in the presence of a suitableinert diluent or carrier as defined hereinbefore and at a temperature inthe range 10 to 150° C., preferably at or near ambient temperature.

-   (k) A compound of the Formula I wherein R² or a substituent on Q or    R⁴ is an amino group may be prepared by the reduction of a compound    of the Formula I wherein R² or a substituent on Q or R⁴ is a nitro    group.

Typical reaction conditions include the use of ammonium formate orhydrogen gas in the presence of a catalyst, for example a metalliccatalyst such as palladium-on-carbon. Alternatively a dissolving metalreduction may be carried out, for example using iron in the presence ofan acid, for example an inorganic or organic acid such as hydrochloric,hydrobromic, sulphuric or acetic acid. The reaction is convenientlycarried out in the presence of an organic solvent (preferably a polarprotic solvent) and preferably with heating, for example to about 60° C.Any functional groups are protected and deprotected as necessary.

The following biological assays and Examples serve to illustrate thepresent invention.

Biological Assays

The following assays can be used to measure the p38 kinase-inhibitory,the TNF-inhibitory and anti-arthritic effects of the compounds of thepresent invention:

In Vitro Enzyme Assay

The ability of compounds of the invention to inhibit the enzyme p38kinase was assessed. Activity of test compounds against each of the p38αand p38β isoforms of the enzyme was determined.

Human recombinant MKK6 (GenBank Accession Number G1209672) was isolatedfrom Image clone 45578 (Genomics, 1996, 33, 151) and utilised to produceprotein in the form of a GST fusion protein in a pGEX vector usinganalogous procedures to those disclosed by J. Han et al., Journal ofBiological Chemistry, 1996, 271, 2886-2891. p38α (GenBank AccessionNumber G529039) and p38β (GenBank Accession Number G1469305) wereisolated by PCR amplification of human lymphoblastoid cDNA (GenBankAccession Number GM1416) and human foetal brain cDNA [synthesised frommRNA (Clontech, catalogue no. 6525-1) using a Gibco superscript cDNAsynthesis kit] respectively using oligonucleotides designed for the 5′and 3′ ends of the human p38α and p38β genes using analogous proceduresto those described by J. Han et al., Biochimica et Biophysica Acta 1995,1265, 224-227 and Y. Jiang et al., Journal of Biological Chemistry.1996, 271, 17920-17926.

Both p38 protein isoforms were expressed in e coli in PET vectors. Humanrecombinant p38α and p38β isoforms were produced as 5′c-myc, 6His taggedproteins. Both MKK6 and the p38 proteins were purified using standardprotocols: the GST MKK6 was purified using a glutathione sepharosecolumn, and the p38 proteins were purified using nickel chelate columns.

The p38 enzymes were activated prior to use by incubation with MKK6 for3 hours at 30° C. The unactivated coli-expressed MKK6 retainedsufficient activity to fully activate both isoforms of p38. Theactivation incubate comprised p38α (10 of 10 mg/ml) or p38β (10 μl of 5mg/nl) together with MKK6 (10 μl of 1 mg/ml), ‘Kinase buffer’ [100 μl;pH 7.4 buffer comprising Tris (50 mM), EGTA (0.1 mM), sodiumorthovanadate (0.1 mM) and β-mercaptoethanol (0.1%)] and MgATP (301l of50 mM Mg(OCOCH₃)₂ and 0.5 mM ATP). This produced enough activated p38enzyme for 3 Microtiter plates.

Test compounds were solubilised in DMSO and 10 μl of a 1:10 dilutedsample in ‘Kinase Buffer’ was added to a well in a Microtiter plate. Forsingle dose testing, the compounds were tested at 10 μM. ‘Kinase AssayMix’ [30 μl; comprising Myelin Basic Protein (Gibco BRL cat. no.1322B-010; 1 ml of a 3.33mg/ml solution in water), activated p38 enzyme(50 μl) and ‘Kinase Buffer’ (2 ml)] was then added followed by ‘LabelledATP’ [10 μl; comprising 50 μM ATP, 0.8 μCi ³³P ATP (AmershamInternational cat. no. BF1000) and 50 mM Mg(OCOCH₃)₂]. The plates wereincubated at room temperature with gentle agitation. Plates containingp38α were incubated for 90 min and plates containing p38β were incubatedfor 45 min. Incubation was stopped by the addition of 50 μl of 20%trichloroacetic acid (TCA). The precipitated protein was phosphorylatedby p38 kinase and test compounds were assessed for their ability toinhibit this phosphorylation. The plates were filtered using a CanberraPackard Unifilter and washed with 2% TCA, dried overnight and counted ona Top Count scintillation counter.

Test compounds were tested initially at a single dose and activecompounds were retested to allow IC₅₀ values to be determined.

In Vitro Cell-Based Assays

(i) PBMC

The ability of compounds of this invention to inhibit TNFα productionwas assessed by using human peripheral blood mononuclear cells whichsynthesise and secrete TNFα when stimulated with lipopolysaccharide.

Peripheral blood mononuclear cells (PBMC) were isolated from heparinised(10 units/ml heparin) human blood by density centrifugation(Lymphopreph™; Nycomed). Mononuclear cells were resuspended in culturemedium [RPMI 1640 medium (Gibco) supplemented with 50 units/mlpenicillin, 50 μg/ml streptomycin, 2 mM glutamine and 1%heat-inactivated human AB serum (Sigma H-1513)]. Compounds weresolubilised in DMSO at a concentration of 50 mM, diluted 1:100 inculture medium and subsequently serial dilutions were made in culturemedium containing 1% DMSO. PBMCs (2.4×10⁵ cells in 160 μl culturemedium) were incubated with 20 μl of varying concentrations of testcompound (triplicate cultures) or 20 μl culture medium containing 1%DMSO (control wells) for 30 minutes at 37° C. in a humidified (5%CO₂/95%air) incubator (Falcon 3072; 96 well flat-bottom tissue culture plates).20μl lipopolysaccharide [LPS E. Coli 0111:B4 (Sigma L-4130), finalconcentration 10 μg/ml] solubilised in culture medium was added toappropriate wells. 20 μl culture medium was added to “medium alone”control wells. Six “LPS alone” and four “medium alone” controls wereincluded on each 96 well plate. Varying concentrations of a known TNFαinhibitor were included in each test, i.e. an inhibitor of the PDE TypeIV enzyme (for example see Semmler, J. Wachtel. H and Endres, S., Int.J. Immunopharmac. (1993), 15(3), 409-413) or an inhibitor of proTNFαconvertase (for example, see McGeehan, G. M. et al. Nature (1994) 370,558-561). Plates were incubated for 7 hours at 37° C. (humidifiedincubator) after which 100 μl of the supernatant was removed from eachwell and stored at −70° C. (96 well round-bottom plates; Corning 25850).TNFα levels were determined in each sample using a human TNFα ELISA (seeWO92/10190 and Current Protocols in Molecular Biology, vol 2 byFrederick M. Ausubel et al., John Wiley and Sons Inc.).% inhibition=(LPS alone−medium alone)−(test concentration−Mediumalone)/(LPS alone−medium alone)×100(ii) Human Whole Blood

The ability of the compounds of this invention to inhibit TNFαproduction was also assessed in a human whole blood assay. Human wholeblood secretes TNFα when stimulated with LPS. This property of bloodforms the basis of an assay which is used as a secondary test forcompounds which profile as active in the PBMC test.

Heparinised (10 units/ml) human blood was obtained from volunteers. 160μl whole blood were added to 96 well round-bottom plates (Corning25850). Compounds were solubilised and serially diluted in RPMI 1640medium (Gibco) supplemented with 50 units/ml penicillin, 50 μg/mlstreptomycin and 2 mM glutamine, as detailed above. 20 μl of each testconcentration was added to appropriate wells (triplicate cultures). 20μl of RPMI 1640 medium supplemented with antibiotics and glutamine wasadded to control wells. Plates were incubated for 30 minutes at 37° C.(humidified incubator), prior to addition of 20 μl LPS (finalconcentration 10 μg/ml). RPMI 1640 medium was added to control wells.Six “LPS alone” and four “medium alone” controls were included on eachplate. A known TNFα synthesis/secretion inhibitor was included in eachtest. Plates were incubated for 6 hours at 37° C. (humidifiedincubator). Plates were centrifuged (2000 rpm for 10 minutes) and 100 μlplasma removed and stored at −70° C. (Corning 25850 plates). TNFα levelswere measured by ELISA (see WO92/10190 and Current Protocols inMolecular Biology vol 2 by Frederick M. Ausubel et al., John Wiley andSons Inc.). The paired antibodies that were used in the ELIZA wereobtained from R&D Systems (catalogue nos. MAB610 anti-human TNFα coatingantibody, BAF210 biotinylated anti-human TNFα detect antibody).

Ex Vivo/In Vivo Assessment

The ability of the compounds of this invention as ex vivo TNFαinhibitors were assessed in the rat or mouse. Briefly, groups of maleWistar Alderley Park (AP) rats (180-210 g) were dosed with compound (6rats) or drug vehicle (10 rats) by the appropriate route, for exampleperoral (p.o.), intraperitoneal (i.p.) or subcutaneous (s.c.). Ninetyminutes later rats were sacrificed using a rising concentration of CO₂and bled out via the posterior vena cavae into 5 Units of sodiumheparin/ml blood. Blood samples were immediately placed on ice andcentrifuged at 2000 rpm for 10 min at 4° C. and the harvested plasmasfrozen at −20° C. for subsequent assay of their effect on TNFαproduction by LPS-stimulated human blood. The rat plasma samples werethawed and 175 μl of each sample was added to a set format pattern in a96 well round bottom plate (Corning 25850). 50 μl of heparinized humanblood was then added to each well, mixed and the plate was incubated for30 min at 37° C. (humidified incubator). LPS (25 μl; final concentration10 μg/ml) was added to the wells and incubation continued for a further5.5 hours. Control wells were incubated with 25 μl of medium alone.Plates were then centrifuged for 10 min at 2000 rpm and 200 μl of thesupernatants were transferred to a 96 well plate and frozen at −20° C.for subsequent analysis of TNF concentration by ELISA.

Data analysis by dedicated software calculates for each compound/dose:

${\%\mspace{14mu}{inhibition}\mspace{14mu}{of}\mspace{14mu}{TNF}\;\alpha} = {\frac{\begin{matrix}{{{Mean}\mspace{14mu}{TNF}\;{\alpha({Controls})}} -} \\{{Mean}\mspace{11mu}{TNF}\;{\alpha({Treated})}}\end{matrix}}{{Mean}\mspace{14mu}{TNF}\;{\alpha({Controls})}} \times 100}$

Alternatively, mice could be used instead of rats in the aboveprocedure.

Test as Anti-Arthritic Agent

Activity of a compound as an anti-arthritic agent was tested as follows.Acid soluble native type II collagen was shown by Trentham et al. [1] tobe arthritogenic in rats; it caused polyarthritis when administered inFreunds incomplete adjuvant. This is now known as collagen-inducedarthritis (CIA) and similar conditions can be induced in mice andprimates. Recent studies have shown that anti-TNF monoclonal antibodies[2] and TNF receptor-IgG fusion proteins [3] ameliorate established CIAindicating that TNF plays a key role in the pathophysiology of CIA.Moreover, the remarkable efficacy reported for anti-TNF monoclonalantibodies in recent rheumatoid arthritis clinical trials indicates thatTNF plays a major role in this chronic inflammatory disease. Thus CIA inDBA/1 mice as described in references 2 and 3 is a tertiary model whichcan be used to demonstrate the anti-arthritic activity of a compound.Also see reference 4.

1. Trentham, D. E. et al., (1977) J. Exp. Med., 146, 857.

2. Williams, R. O. et al., (1992) Proc. Natl. Acad. Sci., 89, 9784.

3. Williams, R. O. et al., (1995) Immunology, 84, 433.

4. Badger, M. B. et al., (1996) The Journal of Pharmacology andExperimental Therapeutics, 279, 1453-1461.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general a compound of theFormula I gives over 30% inhibition of p38α and/or p38β atconcentrations up to 10 μM and over 30% inhibition in the PBMC test atconcentrations up to 50 μM. No physiologically unacceptable toxicity wasobserved at the effective dose for compounds tested of the presentinvention.

By way of example, the compoundN-(3-dimethylaminophenyl)-4-methyl-3,4-propylbenzamido)benzamide[Example 3, Compound No. 1] has an IC₅₀ of approximately 0.3cm againstp38α and an IC₅₀ of approximately 6 μM in the PBMC test; the compoundN-(2-cyclohexylethyl)-3-(3,4-diethoxybenzamido)-4-methylbenzamide[Example 11] has an IC₅₀ of approximately 1 μM against p38α and an IC₅₀of approximately 8 μM in the PBMC test and the compoundN-(3-dimethylaminophenyl)-4-methyl-3,6-quinolylcarbonylamino)benzamide[Example 12] has an IC₅₀ of approximately 0.7 μM against p38α and anIC₅₀ of approximately 22 μM in the PBMC test.

As disclosed hereinbefore, an aspect of the present invention concernscompounds of the Formula I wherein Q is substituted by a basicsubstituent selected from the substituents for Q defined hereinbeforeand R⁴ is, for example, a phenyl group which also bears a basicsubstituent selected from the substituents for R⁴ defined hereinbefore,which compounds possess improved TNFα inhibitory potency in one or bothof the PBMC and HWB tests. By way of example,4-methyl-N-(3-morpholinophenyl)-3-(3-piperidin-4-yloxybenzamido)benzamide[Example 20] has an IC₅₀ of approximately 0.05 μM against p38α and anIC₅₀ of approximately 2 μM in the HWB test;4-methyl-3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-N-(3-morpholinophenyl)benzamide[Example 30] has an IC₅₀ of approximately 0.05 μM against p38α and anIC₅₀ of approximately 5 μM in the HWB test; and4-methyl-3-(4-diethylaminomethylbenzamido)-N-(3-morpholinophenyl)benzamide[Example 31(4)] has an IC₅₀ of approximately 0.3 μM against p38α and anIC₅₀ of approximately 15 μM in the HWB test.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises an amide derivative of theFormula I, or a pharmaceutically-acceptable or in-vivo-cleavable esterthereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent compounded with an appropriate andconvenient amount of excipients which may vary from about 5 to about 98percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred, particularly in tablet form. Typically, unit dosage formswill contain about 1 mg to 500 mg of a compound of this invention.

According to a further aspect of the invention there is provided anamide derivative of the Formula I, or a pharmaceutically-acceptable saltor in-vivo-cleavable ester thereof, as defined hereinbefore for use in amethod of treatment of the human or animal body by therapy.

According to a further aspect of the invention there is provided the useof an amide derivative of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, asdefined hereinbefore in the manufacture of a medicament for use in thetreatment or medical conditions mediated by cytokines.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by cytokines which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by TNF,IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula I or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by TNF.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in inhibiting TNF, IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method ofinhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in inhibiting TNF.

In a further aspect the present invention provides a method ofinhibiting TNF which comprises administering to a warm-blooded animal aneffective amount of a compound of the Formula I, or apharmaceutically-acceptable salt or in vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by p38kinase.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by p38 kinase which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the production of a p38 kinase inhibitory effect.

In a further aspect the present invention provides a method of providinga p38 kinase inhibitory effect which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula 1,or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of rheumatoid arthritis, asthma, irritable boweldisease, multiple sclerosis, AIDS, septic shock, congestive heartfailure, ischaemic heart disease or psoriasis.

In a further aspect the present invention provides a method of treatingrheumatoid arthritis, asthma, irritable bowel disease, multiplesclerosis, AIDS, septic shock, congestive heart failure, ischaemic heartdisease or psoriasis which comprises administering to a warm-bloodedanimal an effective amount of a compound of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.

The compounds of this invention may be used in combination with otherdrugs and therapies used in the treatment of disease states which wouldbenefit from the inhibition of cytokines, in particular TNF and IL-1.For example, the compounds of the Formula I could be used in combinationwith drugs and therapies used in the treatment of rheumatoid arthritis,asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock,congestive heart failure, ischaemic heart disease, psoriasis and theother disease states mentioned earlier in this specification.

For example, by virtue of their ability to inhibit cytokines, thecompounds of the Formula I are of value in the treatment of certaininflammatory and non-inflammatory diseases which are currently treatedwith a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug(NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid,ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of acompound of the Formula I with a NSAID can result in a reduction of thequantity of the latter agent needed to produce a therapeutic effect.Thereby the likelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced. Thus according to a furtherfeature of the invention there is provided a pharmaceutical compositionwhich comprises a compound of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent, and a pharmaceutically-acceptable diluent orcarrier.

The compounds of the invention may also be used with anti-inflammatoryagents such as an inhibitor of the enzyme 5-lipoxygenase.

The compounds of the Formula I may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compounds of the Formula I may be be used in the treatment of asthmain combination with antiasthmatic agents such as bronchodilators andleukotriene antagonists.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofcytokines. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) in general, the end-products of the Formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and/or mass spectral techniques; fast-atom bombardment(FAB) mass spectral data were obtained using a Platform spectrometerand, where appropriate, either positive ion data or negative ion datawere collected; NMR chemical shift values were measured on the deltascale [proton magnetic resonance spectra were determined using a VarianGemini 2000 spectrometer operating at a field strength of 300 MHz or aBruker AM300 spectrometer operating at a field strength of 300 MHz]; thefollowing abbreviations have been used: s, singlet; d, doublet; t,triplet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide DMSO dimethylsulphoxide THF tetrahydrofuran

EXAMPLE 1N-(3-dimethylaminophenyl)-3-(3-methoxybenzamido)-4-methylbenzamide

Triethylamine (0.101 g) was added to a stirred mixture of3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.135 g),3-methoxybenzoyl chloride (0.13 g) and methylene chloride (5 ml) and theresultant mixture was stirred at ambient temperature for 16 hours. Themixture was evaporated and the residue was partitioned between ethylacetate and a saturated aqueous sodium bicarbonate solution. The organicphase was evaporated and the residue was triturated under a mixture ofethyl acetate and isohexane. There was thus obtained the title compoundas a solid (0.156 g); Mass Spectrum: M+H⁺ 404.

The 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide used as astarting material was prepared as follows:

Oxalyl chloride (1.73 ml) and DMF (a few drops) were added in turn to asolution of 4-methyl-3-nitrobenzoic acid (3.0 g) in methylene chloride(30 ml) which had been cooled to 0° C. and the resultant mixture wasstirred at ambient temperature for 3 hours. The mixture was evaporatedand the residue was dissolved in methylene chloride (30 ml).3-Dimethylaminoaniline hydrochloride (2.89 g), 4-dimethylaminopyridine(0.169 g) and triethylamine (7.7 ml) were added in turn and the reactionmixture was stirred at ambient temperature for 16 hours. The reactionmixture was partitioned between methylene chloride and a saturatedaqueous sodium chloride solution. The organic phase was dried overmagnesium sulphate and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol as eluent. There was thus obtainedN-(3dimethylaminophenyl)-4-methyl-3-nitrobenzamide as a yellow solid(3.75 g); NMR Spectrum: (CDCl₃) 2.69 (s, 3H), 3.0 (s, 6H), 6.57 (d, 1H),6.87 (d, 1H), 7.2 (m, 2H), 7.49 (d, 1H), 7.75 (broad s, 1H), 8.05 (d,1H), 8.45 (s, 1H).

10% Palladium-on-carbon (0.369 g) was added to a solution of thematerial so obtained (3.69 g) in methanol (150 ml). Ammonium formate(7.8 g) was added and the resultant mixture was stirred and heated toreflux for 1.25 hours. The mixture was cooled to ambient temperature andfiltered through diatomaceous earth. The filtrate was evaporated and theresidue was triturated under water. The resultant solid was dried undervacuum at 55° C. to give3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide as a white solid(3.04 g); NMR Spectrum: (CDCl₃) 2.22 (s, 3H), 2.98 (s, 6H), 3.75 (broads, 2H), 6.52 (m, 1H), 6.83 (d, 1H), 7.13 (s, 2H), 7.21 (m, 3H), 7.68(broad s, 1H).

EXAMPLE 2N-(3-dimethylaminophenyl)-4-methyl-3-(5-methylisoxazol-3-ylcarbonylamino)benzamide

Triethylamine (0.129 ml) was added to a stirred mixture of3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.1 g),4-dimethylaminopyridine (5 mg), 5-methylisoxazol-3-ylcarbonyl chloride(0.081 g) and methylene chloride (3 ml) and the resultant mixture wasstirred at ambient temperature for 16 hours. The mixture was dilutedwith methylene chloride (10 ml), washed with a saturated aqueous sodiumbicarbonate solution and dried over magnesium sulphate. The organicsolution was evaporated and the residue was triturated under isohexane.The resultant solid was dried at 55° C. under vacuum to give the titlecompound as a solid (0.1 g); NMR Spectrum: (CDCl₃) 2.42 (s, 3H), 2.55(s, 3H), 2.97 (s, 6H), 6.55 (m, 2H), 6.89 (d, 1H), 7.23 (m, 2H), 7.36(d, 1H), 7.72 (d, 1H), 7.84 (broad s, 1H), 8.55 (broad s, 2H); MassSpectrum: M+H⁺ 379.

EXAMPLE 3

Using an analogous procedure to that described in Example 1 or 2, theappropriate benzoyl chloride (prepared by reaction of the correspondingbenzoic acid with oxalyl chloride using an analogous procedure to thatdescribed in the first part of the portion of Example 1 which isconcerned with the preparation of starting materials) was reacted withthe appropriate aniline to give the compounds described in Table I.

TABLE I

No. (R¹)_(m) R Method Note 1 4-propyl 3-dimethylamino Ex. 2 (a) 24-ethyl 3-dimethylamino Ex. 1 (b) 3 3,4-dimethyl 3-dimethylamino Ex. 1(c) 4 4-acetyl 3-dimethylamino Ex. 2 (d) 5 4-methoxy 3-dimethylamino Ex.1 (e) 6 4-ethoxy 3-dimethylamino Ex. 1 (f) 7 3,4-dimethoxy3-dimethylamino Ex. 2 (g) 8 3,4,5-trimethoxy 3-dimethylamino Ex. 2 (h) 94-butoxy 3-dimethylamino Ex. I (i) 10 3-cyano 3-dimethylamino Ex. 1 (j)11 3,4-methylenedioxy 3-dimethylamino Ex. 1 (k) Notes (a) The productgave the following data: NMR Spectrum: (CDCl₃) 0.97(t, 3H), 1.69(m, 2H),2.08(s, 3H), 2.67(t, 2H), 2.96(s, 6H), 6.53(d, 1H), 6.92(d, 1H), 7.1(d,1H), 7.2(t, 2H), 7.34(d, 2H), 7.66(m, 2H), 7.82(d, 2H), 7.94(broad s,1H), 8.4(broad s, 1H); Mass Spectrum: M + H⁺ 416. (b) The product gavethe following data: Mass Spectrum: M + H⁺ 402. (c) The product gave thefollowing data: Mass Spectrum: M + H⁺ 402. (d) The product gave thefollowing data: NMR Spectrum: (CDCl₃) 2.42(s, 3H), 2.67(s, 3H), 2.99(s,6H), 6.57(d, 1H), 6.91(d, 1H), 7.21(m, 2H), 7.37(d, 1H), 7.71(d, 1H),7.9(m, 2H), 8.02(d, 2H), 8.11(d, 2H), 8.37(s, 1H); Mass Spectrum: M + H⁺416. The 4-acetylbenzoyl chloride was prepared as follows:- Oxalylchloride (0.058 ml) was added to a solution of 4-acetylbenzoic acid(0.091 g) in a mixture of methylene chloride (3 ml) and DMF (a fewdrops) and the mixture was stirred at ambient temperature for 6 h. Themixture was evaporated to give the desired compound which was usedwithout further purification. (e) The product gave the following data:Mass Spectrum: M + H⁺ 404. (f) The product gave the following data: MassSpectrum: M + H⁺ 418. (g) The product gave the following data: NMRSpectrum: (DMSOd₆) 2.29(s, 3H), 2.86(s, 6H), 3.83(s, 6H), 6.46(d, 1H),7.12(m, 4H), 7.4(d, 1H), 7.58(broad s, 1H), 7.64(d, 1H), 7.79(d, 1H),7.92(s, 1H), 9.88(s, 1H), 9.96(s, 1H); Mass Spectrum: M + H⁺ 434. (h)The product was purified by column chromatography using increasinglypolar mixtures of methylene chloride and methanol as eluent. Theresultant product gave the following data: NMR Spectrum: (CDCl₃)2.24(s,3H), 2.93(s, 6H), 3.89(s, 9H), 6.5(d, 1H), 6.92(d, 1H), 7.15(m, 5H),7.54(d, 1H), 7.84(broad s, 1H), 8.11(broad s, 1H), 8.32(broad s, 1H);Mass Spectrum: M + H⁺ 465. (i) The product gave the following data: MassSpectrum: M + H⁺ 446. (j) The product gave the following data: MassSpectrum: M + H⁺ 399. (k) The product gave the following data: MassSpectrum: M + H⁺ 418.

EXAMPLE 4N-(3-dimethylaminophenyl)-3-(4-hydroxybenzamido)-4-methylbenzamide

Using an analogous procedure to that described in the last paragraph ofthe portion of Example 1 which is concerned with the preparation ofstarting materials, a mixture of3-(4-benzyloxybenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamide(0.227 g), 10% palladium-on-carbon (0.028 g), ammonium formate (0.37 g)and methanol (20 ml) was stirred and heated to reflux for 1.5 hours. Themixture was cooled to ambient temperature and filtered throughdiatomaceous earth. The filtrate was evaporated and the residue wastriturated under water. The resultant solid was washed with a 100:1:0.12mixture of methylene chloride, methanol and a saturated aqueous ammoniumhydroxide solution and dried under vacuum at 55° C. There was thusobtained the title compound as a solid (0.104 g); NMR Spectrum: (DMSOd₆)2.26 (s, 3H), 2.84 (s, 6H), 6.44 (d, 1H), 6.84 (d, 2H), 7.13 (m, 3H),7.39 (d, 1H), 7.76 (d, 1H), 7.86 (d, 2H), 7.92 (s, 1H), 9.73 (s, 1H),9.91 (s, 1H); Mass Spectrum: M+H⁺ 391.

The 3-(4-benzyloxybenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamideused as a starting material was prepared as follows:

Oxalyl chloride (0.12 ml) was added to a solution of 4-benzyloxybenzoicacid (0.254 g) in a mixture of methylene chloride (5 ml) and DMF (a fewdrops) which had been cooled to 0° C. The resultant mixture was stirredat ambient temperature for 4 hours. The reaction mixture was evaporatedand the residue was dissolved in methylene chloride (6 ml).3-Amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.3 g),4-dimethylaminopyridine (0.014 g) and diisopropylethylamine (0.485 ml)were added in turn and the resultant solution was stirred at ambienttemperature for 16 hours. The reaction mixture was partitioned betweenmethylene chloride and a saturated aqueous sodium chloride solution,dried over magnesium sulphate and evaporated. The residue was purifiedby column chromatography using a 1:1 mixture of isohexane and ethylacetate as eluent. There was thus obtained the required startingmaterial as a solid (0.358 g); NMR Spectrum: (CDCl₃) 2.39 (s, 3H), 2.98(s, 6H), 5.15 (s, 2H), 6.53 (d, 1H), 6.93 (d, 1H), 7.07 (d, 2H), 7.21(m, 2H), 7.40 (m, 6H), 7.72 (m, 2H), 7.9 (m, 3H), 8.40 (s, 1H).

EXAMPLE 5N-(3-dimethylaminophenyl)-3-[4-(2-methoxyethoxy)benzamido]-4-methylbenzamide

2-Bromoethyl methyl ether (0.033 ml) was added to a stirred suspensionof N-(3-dimethylaminophenyl)-3-(4-hydroxybenzamido)-4-methylbenzamide(0.9 g) and anhydrous potassium carbonate (0.064 g) in DMF (10 ml) andthe resultant mixture was stirred at 80° C. for 5 hours. The mixture wascooled to ambient temperature and partitioned between ethyl acetate andwater. The organic phase was washed with a saturated aqueous sodiumbicarbonate solution and with a saturated aqueous sodium chloridesolution, dried over magnesium sulphate and evaporated. The residue wastriturated under diethyl ether. There was thus obtained the titlecompound as a solid (0.073 g); NMR Spectrum: (DMSOd₆) 2.28 (s, 3H), 2.87(s, 6H), 3.31 (s, 3H), 3.67 (m, 2H), 4.18 (m, 2H), 6.43 (d, 1H) 7.12 (m,5H), 7.37 (d, 1H), 7.78 (d, 1H), 7.97 (m, 3H), 9.87 (s, 1H), 9.96 (s,1H); Mass Spectrum: M+H⁺448.

EXAMPLE 64-chloro-N-(3-dimethylaminophenyl)-3-(4-propylbenzamido)benzamide

Using an analogous procedure to that described in Example 1,4-chloro-3-(4-propylbenzamido)benzoyl chloride was reacted with3-dimethylamino aniline dihydrochloride to give the title compound; NMRSpectrum: DMSOd₆) 0.9 (t, 3H), 1.18 (t, 2H), 1.69 (m, 2H), 2.99 (s, 6H),7.0 (d, 1H), 7.2-7.5 (m, 4H) 7.64-7.8 (m, 3H), 7.84 (d, 1H), 8.0 (m,2H), 8.19 (s, 1H); Mass Spectrum: M+H⁺ 436 and 438.

The 4-chloro-3-(4-propylbenzamido)benzoyl chloride used as startingmaterial was prepared as follows:

Acetyl chloride (1.67 ml) was added to a suspension of3-amino-4-chlorobenzoic acid (2.0 g) in methanol (100 ml) and themixture was stirred and heated to reflux for 16 hours. The mixture wasallowed to cool and was evaporated. The residue was partitioned betweenmethylene chloride and a saturated aqueous sodium bicarbonate solution.The organic phase was washed with a saturated aqueous sodium chloridesolution and evaporated. There was thus obtained methyl3-amino-4-chlorobenzoate as a solid (2.13 g) NMR Spectrum: (DMSOd₆) 3.79(s, 3H), 5.62 (s, 2H), 7.06 (d, 1H), 7.29 (d, 1H), 7.4 (s, 2H).

Triethylamine (1.5 ml) was added to a stirred suspension of methyl3-amino-4-chlorobenzoate (1.0 g) and 4-propylbenzoyl chloride (1.34 ml)in methylene chloride (50 ml) and the mixture was stirred at ambienttemperature for 16 hours. The mixture was washed with a saturatedaqueous sodium bicarbonate solution and evaporated. The residue wastriturated under a mixture of ethyl acetate, diethyl ether andisohexane. There was thus obtained methyl4-chloro-3-(4-propylbenzamido)-benzoate as a solid (1.05 g); NMRSpectrum: (DMSOd₆) 0.89 (t, 3H), 1.58-1.66 (m, 2H), 2.63 (t, 2H), 3.86(s, 3H), 7.34 (d, 2H), 7.7 (d, 1H), 7.81 (d, 1H), 7.9 (d, 2H), 8.2 (s,1H), 10.07 (s, 1H).

A 2N aqueous sodium hydroxide solution (3.02 ml) was added to a mixtureof a portion (0.5 g) of the material so obtained, methanol (20 ml) andwater (5 ml) and the resultant mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue wasdissolved in water and extracted with ethyl acetate. The aqueous phasewas acidified to pH2 and the resulting precipitate was isolated andwashed with ethyl acetate and diethyl ether. There was thus obtained4-chloro-3-(4-propylbenzamido)benzoic acid as a solid (0.175 g); NMRSpectrum: (DMSOd₆) 0.89 (t, 3H), 1.58-1.66(m, 2H), 2.62 (t, 2H), 7.36(d, 2H), 7.67 (d, 1H), 7.81 (d, 1H), 7.9 (d, 2H), 8.15 (s, 1H), 10.07(s, 1H), 13.2 (broad s, 1H).

Oxalyl chloride (0.048 ml) was added dropwise to a stirred solution of aportion (0.16 g) of the material so obtained in a mixture of methylenechloride (20 ml) and DMF (a few drops) which had been cooled to 0° C.The mixture was allowed to warm to ambient temperature and was stirredfor 4 hours. The mixture was evaporated to give4-chloro-3-(4-propylbenzamido)benzoyl chloride which was used withoutfurther purification.

EXAMPLE 73-(4-carboxybenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamide

A mixture of3-(4-methoxycarbonylbenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamide(0.15 g), 2N aqueous sodium hydroxide solution (5 ml), methanol (2 ml)and THF (4 ml) was stirred at ambient temperature for 16 hours. Themixture was evaporated and the residue was acidified with 2N aqueoushydrochloric acid. The resultant precipitate was isolated and driedunder vacuum at 55° C. to yield the title compound as a white solid(0.095 g); NMR Spectrum: (DMSOd₆) 2.32 (s, 3H), 3.06 (s, 6H), 7.28(broad s, 1H), 7.43 (m, 2H), 7.7 (d, 1H), 7.84 (d, 1H), 8.0 (d, 2H), 8.1(m, 4H), 10.26 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M+H⁺ 418.

The3-(4-methoxycarbonylbenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamideused as a starting material was obtained as follows:

Triethylamine (0.26 ml) was added to a stirred mixture of4-methoxycarbonylbenzoyl chloride (0.221 g), 4-dimethylaminopyridine(0.01 g), 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.2 g)and methylene chloride (10 ml) and the resultant mixture was stirred atambient temperature for 16 hours. The mixture was diluted with methylenechloride and washed with a saturated aqueous sodium bicarbonate solutionand with a saturated aqueous sodium chloride solution. The organicsolution was dried over magnesium sulphate and evaporated. The residuewas triturated under isohexane. The resultant solid was isolated anddried under vacuum at 55° C. to give the required starting material as asolid (0.286 g); NMR Spectrum: (CDCl₃) 2.4 (s, 3H), 2.98 (s, 6H), 3.98(s, 3H), 6.54 (m, 1H), 6.92 (d, 1H), 7.2 (m, 3H), 7.35 (d, 1H), 7.71 (d,1H), 7.92 (s, 1H), 7.98 (d, 2H), 8.18 (d, 2H), 8.35 (s, 1H).

EXAMPLE 8N-[2-(4-chlorophenoxy)ethyl]-3-(3,4-dimethoxybenzamido)-4-methylbenzamide

A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.095 g) in methylene chloride (5 ml) was added to astirred mixture of 3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid(0.157 g), 2-(4-chlorophenoxy)ethylamine (C. Chim. Ther., 1973, 8, 259;0.086 g), 4-dimethylaminopyridine (0.007 g), 1-hydroxybenzotriazole(0.074 g) and methylene chloride (5 ml). The resultant mixture wasstirred at ambient temperature for 16 hours. The mixture was evaporatedand the residue was partitioned between ethyl acetate and a saturatedaqueous sodium bicarbonate solution. The organic phase was washed withan aqueous citric acid solution, dried over magnesium sulphate andevaporated. There was thus obtained the title compound as a solid (0.158g); Mass Spectrum: M+H⁺ 469.

The 3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid used as a startingmaterial was obtained as follows:

Oxalyl chloride (10.5 ml) was added to a solution of3,4-dimethoxybenzoic acid (18.2 g) in a mixture of methylene chloride(250 ml) and DMF (0.5 ml) which had been cooled to 0° C. The reactionmixture was allowed to warm to ambient temperature and was stirred for4.5 hours. The mixture was evaporated and the residue was dissolved inmethylene chloride (250 ml) and cooled to 0° C. Methyl3-amino-4-methylbenzoate (11.0 g), 4-dimethylaminopyridine (0.81 g) andtriethylamine (23.2 ml) were added and the reaction mixture was stirredat ambient temperature for 65 hours. The reaction mixture was washed inturn with 2N aqueous hydrochloric acid and with a saturated aqueoussolution of sodium bicarbonate, dried over magnesium sulfate, andevaporated. There was thus obtained methyl3-(3,4-dimethoxybenzamido)-4-methylbenzoate as a solid (28.6 g); NMRSpectrum: (CDCl₃) 2.4 (s, 3H), 3.85 (m, 6H), 3.96 (s, 3H), 6.76 (d, 1H),7.2-8.5 (m, 6H).

A solution of the material so obtained in a mixture of 2N aqueous sodiumhydroxide solution (300 ml) and methanol (200 ml) was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the reactionmixture was partitioned between isohexane and water. The aqueous layerwas acidified with aqueous hydrochloric acid and the resultantprecipitate was isolated and dried under vacuum at 55° C. to give3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid as a solid (25.05 g);NMR Spectrum: (DMSOd₆) 2.28 (s, 3H), 3.8 (m, 6H), 7.0-7.8 (m, 6H), 7.89(s, 1H), 9.95 (s, 1H).

EXAMPLE 9 N-cyclobutyl-3-(3,4-dimethoxybenzamido)-4-methylbenzamide

Using an analogous procedure to that described in Example 8,3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid was reacted withcyclobutylamine to give the title compound; Mass Spectrum: M+H⁺ 369.

EXAMPLE 10N-(3,4-dichlorobenzyl)-3-(3,4,5-trimethoxybenzamido)-4-methylbenzamide

Using an analogous procedure to that described in Example 2,3,4,5-trimethoxybenzoyl chloride was reacted with3-amino-N-(3,4-dichlorobenzyl)-4-methylbenzamide to give the titlecompound which was purified by column chromatography using increasinglypolar mixtures of methylene chloride and methanol as eluent; NMRSpectrum: (CDCl₃) 2.28 (s, 3H), 3.87 (m, 9H), 4.48 (d, 2H), 7.13 (m,5H), 7.36 (m, 2H), 7.52 (d, 1H), 8.01 (s, 1H), 8.13 (s, 1H); MassSpectrum: M−H⁻503.

The 3-amino-N-(3,4-dichlorobenzyl)-4-methylbenzamide used as a startingmaterial was obtained as follows:

Oxalyl chloride (4.8 ml) was added to a solution of3-nitro-4-methylbenzoic acid (9.06 g) in methylene chloride (100 ml) andDMF (a few drops) and the reaction stirred at ambient temperature for 16hours. The reaction mixture was evaporated and the residue was dissolvedin methylene chloride (100 ml). 3,4-Dichlorobenzylamine (7.04 g),4-dimethylaminopyridine (0.31 g) and triethylamine (13.9 ml) were addedand the reaction mixture was stirred at ambient temperature for 16hours. The mixture was washed with a saturated aqueous sodiumbicarbonate solution, dried over magnesium sulphate and evaporated Theresidue was purified by column chromatography using a 250:8:1 mixture ofmethylene chloride, methanol and a saturated aqueous ammonium chloridesolution as eluent to giveN-(3,4-dichlorobenzyl)-4-methyl-3-nitrobenzamide as a solid (9.95 g);NMR Spectrum: (DMSOd₆) 2.57 (s, 3H), 4.47 (d, 2H), 7.31 (m, 1H), 7.56(m, 2H), 7.61 (d, 1H), 8.1 (m, 1H), 8.47 (d, 1H), 9.3 (t, 1H).

A solution of stannous chloride dihydrate (17.5 g) in concentratedhydrochloric acid (40 ml) was added to a solution ofN-(3,4-dichlorobenzyl)-4-methyl-3-nitrobenzamide (5.85 g) in ethanol (40ml) and concentrated hydrochloric acid (40 ml). The reaction mixture wasstirred and heated to reflux for 4 hours. The mixture was cooled anddiluted with 2N aqueous hydrochloric acid. The reaction mixture wasextracted several times with ethyl acetate, and the combined organicextracts were washed with a saturated solution of sodium bicarbonate,dried over magnesium sulphate and evaporated to give the requiredstarting material as a solid (3.9 g); NMR Spectrum: (CDCl₃) 2.2 (s, 3H),3.74 (broad s, 2H), 4.58 (d, 2H), 6.4 (broad s, 1H), 7.02 (d, 1H), 7.1(d, 1H), 7.19 (m, 2H), 7.42 (m, 2H).

EXAMPLE 11N-(2-cyclohexylethyl)-3-(3,4-dimethoxybenzamido)-4-methylbenzamide

Ammonium formate (0.224 g) was added to a stirred mixture of 10%palladium-on-carbon (0.015 g),N-(2-cyclohexen-1-ylethyl)-3-(3,4-dimethoxybenzamido)-4-methylbenzamide(0.15 g) and methanol (15 ml) and the reaction mixture was heated toreflux for 1.25 hours. The reaction mixture was allowed to cool and wasfiltered through diatomaceous earth. The filtrate was evaporated and theresidue was triturated under water. The solid so obtained was driedunder vacuum at 55° C. to give the title compound as a powder (0.136 g);NMR Spectrum: (CDCl₃) 0.8-2.3 (m, 13H), 2.37 (s, 3H), 3.45 (m, 2H), 3.96(m, 6H), 6.12 (m, 1H), 6.93 (d, 1H), 7.26 (m, 1H), 7.46 (d, 1H), 7.56(m, 2H), 7.92 (s, 1H), 8.16 (s, 1H); Mass Spectrum: M+H⁺ 425.

TheN-(2-cyclohexen-1-ylethyl)-3-(3,4-dimethoxybenzamido)-4-methylbenzamideused as a starting material was obtained as follows:

2-Cyclohexen-1-ylethylamine (0.146 ml) was added to a stirred mixture of3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid (0.3 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.274 g),4-dimethylaminopyridine (0.012 g) and methylene chloride (5 ml) and thereaction mixture was stirred at ambient temperature for 16 hours. Themixture was partitioned between methylene chloride and 2N aqueoushydrochloric acid. The organic phase was washed with a. saturatedaqueous sodium bicarbonate solution, dried over magnesium sulphate andevaporated. There was thus obtained the required starting material as asolid (0.28 g); NMR Spectrum: (CDCl₃) 1.6 (m, 4H), 2.0 (m, 4H), 2.23 (m,2H), 2.37 (s, 3H), 3.51 (m, 2H), 3.96 (m, 6H), 5.54 (bs, 1H), 6.21(broad s, 1H), 6.94 (d, 1H), 7.21 (m, 1H), 7.43 (m, 1H), 7.55 (m, 2H),7.81 (broad s, 1H), 8.2 (broad s, 1H).

EXAMPLE 12N-(3-dimethylaminophenyl)-4-methyl-3-(6-quinolylcarbonylamino)benzamide

Using an analogous procedure to that described in Example 2,6-quinolylcarbonyl chloride was reacted with3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the titlecompound; NMR Spectrum: (DMSOd₆) 2.35 (s, 3H), 2.91 (s, 6H), 6.58 (m,1H), 7.2 (m, 2H), 7.43 (d, 1H), 7.65 (m, l1H), 7.82 (d, 1H), 8.01 (s,l1H), 8.17 (m, 2H), 8.32 (d, 1H), 8.59 (d, 1H), 8.7 (d, 1H), 9.02 (s,1H), 10.05 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H⁺425.

The 6-quinolylcarbonyl chloride used as a starting material was preparedas follows:

Oxalyl chloride (0.058 ml) was added to a solution of6quinolinecarboxylic acid (0.096 g) in a mixture of methylene chloride(4 ml) and DMF (a few drops) and the reaction mixture was stirred atambient temperature for 6 hours. The mixture was evaporated to give therequired starting material which was used without further purification.

EXAMPLE 134-chloro-N-(3-dimethylaminophenyl)-3-(6-quinolylcarbonylamino)benzamide

Using an analogous procedure to that described in Example 1,4-chloro-3-(6-quinolylcarbonylamino)benzoyl chloride was reacted with3-dimethylaminoaniline dihydrochloride to give the title compound; NMRSpectrum: (DMSOd₆) 3.04 (s, 6H), 6.5 (d, 1H), 7.08-7.20(m, 3H),7.61-7.64 (m, 1H), 7.74 (d, 1H), 7.92 (d, 1H) 8.1-8.2 (m, 2H), 7.31 (d,1H), 8.58 (d, 1H), 8.72 (s, 1H), 9.02 (s, 1H) 10.13 (s, 1H), 10.5 (s,1H); Mass Spectrum: Mass Spectrum: M+H⁺ 445 and 447.

The 4-chloro-3-(6-quinolylcarbonylamino)benzoyl chloride used asstarting material was prepared as follows:

Triethylamine (4.18 ml) was added to a stirred suspension of methyl(3-amino-4-chloro)benzoate (1.85 g) and 6-quinolylcarbonyl chloride(2.88 g) in methylene chloride (80 ml) and the resultant mixture wasstirred at ambient temperature for 16 hours. The mixture was washed witha saturated aqueous sodium bicarbonate solution, dried over magnesiumsulphate and evaporated. The residue was triturated under a mixture ofethyl acetate and diethyl ether. There was thus obtained methyl4-chloro-3-(6-quinolylcarbonylamino)benzoate as a solid (1.1 g); NMRSpectrum: (DMSOd₆) 3.87 (s, 3H), 7.62-7.65 (m, 1H), 7.4 (d, 1H), 7.85(d, 1H), 8.14 (d, 1H), 8.23-8.32 (m, 2H), 8.54 (d, 1H) 8.68 (s, 1H) 9.01(s, 1H), 10.5 (s, 1H).

A 2N aqueous sodium hydroxide solution (2.21 ml) was added to a portion(0.5 g) of the material so obtained in a mixture of methanol (20 ml) andwater (5 ml) and the resultant mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue wasdissolved in water and extracted with ethyl acetate The aqueous phasewas acidified to pH2 by the addition of dilute hydrochloric acidsolution. The resultant precipitate was isolated and washed with diethylether. There was thus obtained4-chloro-3-(6-quinolylcarbonylamino)benzoic acid hydrochloride salt as asolid (0.329 g); NMR Spectrum: (DMSOd₆) 7.64-7.68 (m, 1H), 7.7 (d, 1H),7.83 (d, 1H),8.14-8.19 (m, 2H), 8.29 (d, 1H), 8.57 (d, 1H) 8.7 (s, 1H)9.03 (s, 1H).

Oxalyl chloride (0.048 ml) was added dropwise to a stirred solution of aportion (0.181 g) of the acid so obtained in a mixture of methylenechloride (20 ml) and DMF (a few drops) which had been cooled to 0° C.The mixture was allowed to warm to ambient temperature and was stirredfor 4 hours. The solvent was evaporated to give4-chloro-3-(6-quinolylcarbonylamino)benzoyl chloride which was usedwithout further purification.

EXAMPLE 143-(6-chloropyrid-3-ylcarbonylamino)-N-(3-dimethylaminophenyl)-4-methylbenzamide

Using an analogous procedure to that described in Example 1,6-chloropyrid-3-ylcarbonyl chloride was reacted with3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the titlecompound; Mass Spectrum: M+H⁺ 409 and 411.

EXAMPLE 15N-(3-dimethylaminophenyl)-4-methyl-3-(2-naphthoylamino)benzamide

Using an analogous procedure to that described in Example 1, 2-naphthoylchloride was reacted with3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the titlecompound; Mass Spectrum: M+H⁺ 424.

EXAMPLE 163-(3-benzyloxybenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide

Oxalyl chloride (1.24 ml) was added to a mixture of 3-benzyloxybenzoicacid (2.736 g), DMF (1 ml) and methylene chloride which had been cooledto 0° C. and the resultant mixture was stirred at ambient temperaturefor 4 hours. The mixture was evaporated and a solution of the residue inmethylene chloride (60 ml) was added slowly to a stirred mixture of3-amino-4-methyl-N-(3-morpholinophenyl)benzamide (3.11 g), pyridine(1.69 ml) and methylene chloride (60 ml). The resultant mixture wasstirred at ambient temperature for 12 hours. The mixture was washed inturn with water and with a saturated aqueous sodium bicarbonatesolution, dried over magnesium sulphate and evaporated. The residue wasstirred under diethyl ether (200 ml) for 12 hours and the resultantsolid was isolated. There was thus obtained the title compound (4.5 g);NMR Spectrum: (DMSOd₆) 2.26 (s, 3H), 3.07 (t, 4H), 3.72 (t, 4H), 5.19(s, 2H), 6.66 (d, 1H), 7.3 (m, 11H), 7.6 (t, 2H), 7.78 (d, 1H), 7.95 (s,1H), 10.0 (d, 2H); Mass Spectrum: M+H⁺ 522.

The 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide used as a startingmaterial was prepared as follows:

A mixture of 3-fluoronitrobenzene (13.2 g), morpholine (45 ml) and DMSO(156 ml) was stirred and heated at 100° C. for 4 days. The mixture wascooled and poured into water.

The resultant solid was isolated and dried under vacuum. There was thusobtained 3-morpholinonitrobenzene (14.69 g); NMR Spectrum: (CDCl₃) 3.25(t, 4H), 3.9 (t, 4H), 7.15-7.2 (m, 1H), 7.4 (t, 1H), 7.65-7.75 (m, 2H).

Ammonium formate (22.2 g) was added to a mixture of the material soobtained, 10% palladium-on-carbon (2.1 g) and methanol (250 ml) and theresultant mixture was stirred at ambient temperature for 1 hour. Themixture was evaporated and the residue was partitioned between ethylacetate and water. The organic phase was dried over magnesium sulphateand evaporated. The solid so obtained was washed with isohexane. Therewas thus obtained 3-morpholinoaniline (9.9 g); NMR Spectrum: (CDCl₃)3.04 (t, 4H), 3.68 (t, 4H), 3.5 (br m, 2H), 6.17 (m, 2H), 6.24 (m, 1H),6.98 (t, 1H).

Triethylamine (20 ml) was added to a mixture of 3-morpholinoaniline (9.9g), 4-methyl-3-nitrobenzoyl chloride (8.92 ml) and methylene chloride(400 ml) and the resultant mixture was stirred at ambient temperaturefor 68 hours. The mixture was evaporated. Methylene chloride and asaturated aqueous sodium bicarbonate solution were added and theresultant precipitate was isolated, washed with diethyl ether and driedunder vacuum. There was thus obtained4-methyl-3-nitro-N-(3-morpholinophenyl)benzamide (18.24 g); NMRSpectrum: (DMSOd₆) 2.6 (s, 3H), 3.0-3.1 (m, 4H), 3.7-3.8 (m, 4H),6.7-6.75 (m, 1H), 7.2 (t, 1H), 7.25-7.3 (m, 1H), 7.4 (s, 1H), 7.65 (d,1H), 8.15-8.25 (m, 1H), 8.55 (s, 1H), 10.3-10.33 (s, 1H); Mass Spectrum:M+H⁺ 342.

Ammonium formate (16.8 g) was added to a mixture of the material soobtained, 10% palladium-on-carbon (1.6 g) and methanol (200 ml) whichhad been cooled in an ice-bath. The resultant mixture was stirred atambient temperature for 1.5 hours. The mixture was filtered and thefiltrate was evaporated. The residue was dissolved in methylene chlorideand dried over magnesium sulphate. The solution was evaporated to givethe required starting material (7.34 g); NMR Spectrum: (DMSOd₆) 3.0-3.1(m, 7H), 3.7-3.8 (m, 4H), 5.0 (s, 2H), 6.6-6.7 (m, 1H), 7.05 (s, 2H),7.1-7.2 (m, 2H), 7.25-7.3 (m, 1H), 7.35-7.4 (m, 1H), 9.8 (s, 1H); MassSpectrum: M+H⁺ 312.

EXAMPLE 173-(3-hydroxybenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide

A mixture of3-(3-benzyloxybenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide (4.49g), 10% palladium-on-carbon (0.5 g) and ethyl acetate was stirred underan atmosphere of hydrogen gas for 12 hours. The resultant mixture wasfiltered through diatomaceous earth and the separated solids were washedwith warm DMF (200 ml). The combined filtrates were concentrated to avolume of about 20 ml and water (50 ml) was added. The resultant solidwas dried under vacuum at 55° C. There was thus obtained the titlecompound as a solid (2.99 g); NMR Spectrum: (DMSOd₆) 2.25 (s, 3H), 3.07(t, 4H), 3.72 (t, 4H), 6.67 (m, 1H), 6.97 (m, 1H), 7.18 (t, 1H), 7.36(m, 6H), 7.78 (m, 1H), 7.92 (s, 1H), 9.68 (s, 1H), 9.89 (s, H), 10.01(s, 1H); Mass Spectrum: M+H⁺ 432.

EXAMPLE 183-[3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamido]-4-methyl-N-(3-morpholinophenyl)benzamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g) wasadded to a stirred mixture of3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid (0.307 g),3-amino-4-methyl-N-(3-morpholinophenyl)benzamide (0.312 g),1-hydroxybenztriazole (0.202 g) and DMF (5 ml) which had been cooled to0° C. The resultant reaction mixture was stirred at ambient temperaturefor 40 hours. The mixture was partitioned between ethyl acetate andwater. The organic phase was washed with water and with a saturatedaqueous sodium bicarbonate solution, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicagel using a 3:1 mixture of isohexane and ethyl acetate as eluent. Therewas thus obtained the title compound as a solid (0.31 g); NMR Spectrum:(DMSOd₆) 1.38 (s, 9H), 2.12 (m, 2H), 2.27 (s, 3H), 3 08 (t, 4H), 3.37(m, 3H), 3.57 (m, 1H), 3.74 (t, 4H), 5.05 (m, 1H), 6.67 (d, 1H), 7.17(m, 2H), 7.3 (d, 1H), 7.42 (m, 3H), 7.52 (s, 1H), 7.57 (d, 1H), 7.78 (d,1H), 7.93 (s, 1H), 10.0 (s, 1H), 10.01 (s, 1H); Mass Spectrum: M+H⁺ 601.

The 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid used as astarting material was obtained as follows:

Using an analogous procedure to that described in the first paragraph ofthe portion of Example 25 which is concerned with the preparation ofstarting materials, N-tert-butoxycarbonyl-3-hydroxypyrrolidine (J. Amer.Chem. Soc., 1982, 104, 5852-5853) was reacted with ethyl3-hydroxybenzoate. The product so obtained was hydrolysed with sodiumhydroxide using an analogous procedure to that described in the secondparagraph of the portion of Example 25 which is concerned with thepreparation of starting materials. There was thus obtained the requiredstarting material; NMR Spectrum: (DMSOd₆) 1.38 (s, 9H), 2.06 (m, 2H),3.1 (m, 3H), 3.55 (m, 1H), 5.03 (broad s, 1H), 7.18 (m, 1H), 7.38 (m,2H), 7.52 (d, 1H); Mass Spectrum: M+H⁺ 308.

EXAMPLE 194-methyl-N-(3-morpholinophenyl)-3-(3-pyrrolidin-3-yloxybenzamido)benzamide

Trifluoroacetic acid (0.6 ml) was added to a stirred solution of3-[3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamido]-4-methyl-N-(3-morpholinophenyl)benzamide(0.3 g) in methylene chloride (6 ml) which had been cooled to 0° C. Thereaction mixture was stirred at ambient temperature for 3 hours. Themixture was evaporated and the residue was triturated under diethylether to give the title compound, as its trifluoroacetate salt. Thesolid so obtained was dissolved in water (15 ml) and basified by theaddition of potassium carbonate. The resultant precipitate wascollected, washed with water and dried under vacuum to give the titlecompound (0.18 g); NMR Spectrum: (DMSOd₆) 1.76 (m, 1H), 2.02 (m, 1H),2.23 (s, 3H), 2.83 (m, 2H), 3.06 (m, 5H), 3.55 (m, 1H), 3.76 (t, 4H),4.98 (m, 1H), 6.62 (d, 1H), 7.12 (m, 2H), 7.31 (d, 1H), 7.4 (m, 3H),7.52 (m, 2H), 7.78 (d,. 1H), 7.99 (s, 1H), 10.07 (s, 1H), 10.08 (s, 1H);Mass Spectrum: M+H⁺ 501.

EXAMPLE 204-methyl-N-(3-morpholinophenyl)-3-(3-piperidin-4-yloxybenzamido)benzamide

Using an analogous procedure to that described in Example 18,3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give3-[3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamido]-4-methyl-N-(3-morpholinophenyl)benzamidein 42% yield; NMR Spectrum: (DMSOd₆) 1.38 (s, 9H), 1.54 (m, 2H), 1.91(m, 2H), 2.27 (s, 3H), 3.06 (t, 4H), 3.2 (m, 2H), 3.64 (m, 2H), 3.72 (t,4H), 5.01 (m, 1H), 6.66 (m, 1H), 7.18 (m, 2H), 7.28 (d, 1H), 7.4 (m,3H), 7.56 (m, 2H), 7.77 (m, 1H), 7.92 (s, 1H), 9.98 (s, 1H), 10.01 (s,1H).

The product so obtained was treated with trifluoroacetic acid using ananalogous procedure to that described in Example 19. There was thusobtained the title compound in 81% yield; NMR Spectrum: (DMSOd₆) 1.45(m, 2H), 1.91 (m, 2H), 2.27 (s, 3H), 2.58 (m, 2H), 2.93 (m, 2H), 3.05(t, 4H), 3.71 (t, 4H), 4.46 (m, 1H), 6.67 (m, 1H), 7.16 (m, 2H), 7.25(d, 1H), 7.4 (m, 3H), 7.52 (m, 2H), 7.78 (m, 1H), 7.92 (s, 1H), 9.98 (s,1H), 10.02 (s, 1H); Mass Spectrum: M+H⁺ 515.

The 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid used as astarting material was obtained as follows:

N-tert-Butoxycarbonyl-4-hydroxypiperidine was obtained from a commercialsource, for example from Neosystem, F67100, Strasbourg, France, or wasprepared by the following procedure. A solution of di-tert-butyldicarbonate (53.9 g) in methylene chloride (100 ml) was added dropwiseto a stirred mixture of 4-hydroxypiperidine (25 g), triethylamine (50ml) and methylene chloride (250 ml) which had been cooled to 0° C. Theresultant mixture was allowed to warm to ambient temperature and wasstirred for 18 hours. The mixture was evaporated and the residue waspurified by chromatography on silica a 2:1 mixture of isohexane andethyl acetate as eluent. The oil so obtained was dried under vacuum at60° C. to give N-tert-butoxycarbonyl-4-hydroxypiperidine as a whitesolid (49.1 g); NMR Spectrum: (DMSOd₆) 1.39 (s, 9H), 1.55 (m, 2H), 1.78(m, 2H), 2.95 (m, 2H), 3.76 (m, 2H).

Diethyl azodicarboxylate (1.95 ml) was added dropwise over 5 minutes toa stirred mixture of N-tert-butoxycarbonyl-4-hydroxypiperidine (2 g),ethyl 3-hydroxybenzoate (1.66 g), triphenylphosphine (3.2 g) and THF (40ml) which had been cooled to 0° C. The mixture was stirred at ambienttemperature for 40 hours. The solvent was evaporated and the residue wastriturated under a 9:1 mixture (40 ml) of isohexane and ethyl acetate.The mixture was filtered and the filtrate was evaporated. The residuewas purified by column chromatography on silica using a 9:1 mixture (40ml) of isohexane and ethyl acetate as eluent. There was thus obtainedethyl 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate as an oil (1.82g); NMR Spectrum: (CDCl₃) 1.41 (t, 3H), 1.46 (s, 9H), 1.93 (m, 2H), 3.38(m, 2H), 3.7 (m, 2H), 4.36 (q, 2H), 4.52 (m, 1H), 7.1 (m, 1H), 7.35 (t,3H), 7.58 (s, 1H), 7.62 (d, 1H).

Sodium hydroxide solution (10M; 1.0 ml) was added to a solution inethanol (10 ml) of the ester so obtained and the mixture was stirred atambient temperature for 18 hours. The mixture was evaporated and theresidue was dissolved in water (5 ml). A 1M aqueous hydrochloric acidsolution (10 ml) and glacial acetic acid (1 ml) were added in turn andthe mixture was extracted with methylene chloride. The organic phase wasdried over magnesium sulphate and evaporated to give the requiredstarting material as a colourless solid (1.32 g), m.p. 148-150° C.; MassSpectrum: M+H⁺ 322.

EXAMPLE 213-(3-acetoxybenzamido)-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide

Oxalyl chloride (0.7 ml) was added to a stirred mixture of3-acetoxybenzoic acid (1.242 g), DMF (1 ml) and methylene chloride (40ml) and the solution was stirred at ambient temperature for 2 hours. Themixture was evaporated and a solution of3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (2 g) andpyridine (10 ml) was added to the residue. The resultant mixture wasstirred and heated to 100° C. for 18 hours. The mixture was cooled toambient temperature and washed in turn with an aqueous acetic acidsolution, with water and with a saturated aqueous sodium bicarbonatesolution, dried over magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica gel using a 49:1 mixture ofmethylene chloride and methanol as eluent. There was thus obtained thetitle compound (1.3 g); NMR Spectrum: (DMSOd₆) 2.3 (s, 3H), 3.15 (t,4H), 3.7 (t, 4H), 6.55 (d, 1H), 7.18 (m, 2H), 7.38 (m, 1H), 7.6 (t, 1H),7.72 (m, 2H), 7.89 (m, 2H), 8.16 (s, 1H), 10.3 (d, 2H); Mass Spectrum:M+H⁺ 512.

The 3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide used as astarting material was prepared as follows:

A mixture of 3,5-difluoronitrobenzene (31.1 g) and morpholine (85.2 g)was stirred and heated at 100° C. for 66 hours. The mixture wasevaporated and the residue was purified by column chromatography onsilica gel using a 4:1 mixture of isohexane and ethyl acetate as eluent.There was thus obtained 3-fluoro-5-morpholinonitrobenzene (33.3 g); NMRSpectrum: (DMSOd₆) 3.2-3.3 (m, 4H), 3.6-3.8 (m, 4H), 7.25 (m, 1H), 7.37(m, 1H), 7.5 (m, 1H).

A mixture of the material so obtained, 10% palladium-on-carbon (3.3 g)and ethanol (1400 ml) was stirred under an atmosphere pressure ofhydrogen gas for 16 hours. The mixture was filtered and the filtrate wasevaporated to give 3-fluoro-5-morpholinoaniline (27.5 g); NMR Spectrum:(DMSOd₆) 2.9-3.05 (m, 4H), 3.6-3.7 (m, 4H), 5.15 (s, 2H), 5.75-5.9 30(m, 3H).

A solution of 4-chloro-3-nitrobenzoyl chloride (41.2 g) in methylenechloride (120 ml) was added to a mixture of 3-fluoro-5-morpholinoaniline(27 g), triethylamine (52.6 ml) and methylene chloride (600 ml) whichhad been cooled in an ice-bath. The resultant mixture was stirred atambient temperature for 16 hours. The mixture was evaporated. Methylenechloride and a saturated aqueous sodium bicarbonate solution were addedand the resultant precipitate was isolated, washed with diethyl etherand dried under vacuum. There was thus obtained4-chloro-3-nitro-N-(3-fluoro-5-morpholinophenyl)benzamide (36.1 g); NMRSpectrum: (DMSOd₆) 3.05-3.15 (m, 4H), 3.7-3.75 (m, 4H), 6.5-6.6 (m, 1H),7.1-7.2 (m, 2H), 7.95 (d, 1H), 8.2-8.3 (m, 1H), 8.6 (s, 1H).

A mixture of the material so obtained, iron powder(50.6 g), glacialacetic acid (19 ml), water(95 ml) and ethanol (600 ml) was stirred andheated to reflux for 6 hours. The mixture was cooled to ambienttemperature and water was added. The mixture was carefully basified topH9 by the addition of a saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate. The organic phase was dried overmagnesium sulphate and evaporated to give the required starting material(24.3 g); NMR Spectrum: (DMSOd₆) 3.0-3.1 (m, 4H), 3.7-3.75 (m, 4H), 5.6(s, 1H), 6.45-6.55 (m, 1H), 7.0-7.2 (m, 3H), 7.3-7.35 (m, 2H), 10.09 (brs, 1H); Mass Spectrum: M+H⁺ 350.

EXAMPLE 224-chloro-N-(3-fluoro-5-morpholinophenyl)-3-(3-hydroxybenzamido)benzamide

Sodium methoxide (95%, 0.26 g) was added to a stirred solution of3-(3-acetoxybenzamido)-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide(1.23 g) in methanol (75 ml) which had been cooled to 0° C. Theresultant solution was stirred at ambient temperature for three hours.The mixture was concentrated by evaporation to a volume of about 15 mland water (20 ml) was added. The solution was acidified to pH3 by theaddition of 1N aqueous hydrochloric acid solution. The precipitate soformed was isolated and dried under vacuum. There was thus obtained thetitle compound (0.86 g); NMR Spectrum: (DMSOd₆) 2.47 (s, 3H), 3.08 (t,4H), 3.7 (t, 4H), 6.53 (d, 1H), 6.98 (m, 1H), 7.14 (s, 1H), 7.19 (d,1H), 7.33 (m, 1H), 7.42 (d, 1H), 7.70 (d, 1H), 7.84 (m, 1H), 8.15 (d,1H), 9.75 (s, 1H), 10.08 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M+H⁺470.

EXAMPLE 233-[2-amino-5-(4-methylpiperazin-1-yl)benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide

Iron powder (0.726 g) was added to a stirred suspension of4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[5-(4-methylpiperazin-1-yl)-2-nitrobenzamido]benzamide(0.76 g), water (2 ml), acetic acid (0.5 ml) and ethanol (15 ml) and theresultant mixture was stirred and heated to reflux for 1 hour. Themixture was cooled to ambient temperature. Water (80 ml) was added andthe mixture was basified by the addition of sodium carbonate. Theresultant mixture was filtered through diatomaceous earth and theseparated solids were washed in turn with methylene chloride andmethanol. The combined filtrates were evaporated and the residue wastriturated under ethyl acetate. The mixture was filtered and thefiltrate was evaporated to give the title compound (0.385 g); MassSpectrum: M+H⁺ 567.

The4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[5-(4-methylpiperazin-1-yl)-2-nitrobenzamido]benzamideused as a starting material was prepared as follows:

Oxalyl chloride (1.05 ml) was added dropwise to a stirred mixture of5-chloro-2-nitrobenzoic acid (2.08 g), methylene chloride (100 ml) andDMF (a few drops) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for four hours. Themixture was evaporated and the residue was dissolved in methylenechloride (10 ml) and added dropwise to a stirred mixture of3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (3.0 g) andpyridine (40 ml). The resultant mixture was heated at 80° C. for 16hours. The solvent was evaporated and the residue was dissolved inmethylene chloride (50 ml) and water (50 ml) and stirred for one hour.The resultant solid was filtered, washed with water and diethyl etherand dried under vacuum at 40° C. There was thus obtained4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide(1.07 g); NMR Spectrum: (DMSOd₆) 3.09-3.14 (m, 4H), 3.69-3.74 (m, 4H),6.58 (d, 1H), 7.15-7.2 (m, 2H), 7.71 (d, 1H), 7.82-7.92 (m, 3H), 8.2 (d,1H), 8.29 (s, 1H), 10.37 (s, 1H), 10.61 (s, 1H); Mass Spectrum: M+H⁺ 533and 535.

A portion (0.8 g) of the material so obtained was dissolved in1-methylpiperazine (3 ml) and the mixture was stirred and heated to 100°C. for 16 hours. The mixture was cooled and poured into water. Theresultant solid was isolated, washed in turn with water and diethylether and dried under vacuum at 40° C. There was thus obtained therequired starting material (0.803 g); NMR Spectrum: (DMSOd₆) 2.21 (s,3H), 2.4-2.45 (m, 4H), 3.08-3.13 (m, 4H), 3.46-3.5 (m, 4H), 3.69-3.74(m, 4H), 6.58 (d, 1H), 6.84 (s, 1H), 7.0-7.2 (m, 4H), 7.68 (d, 1H), 7.80(d, 1H), 8.04 (d, 1H), 8.36 (s, 1H); Mass Spectrum: M+H⁺ 597.

EXAMPLE 244-chloro-3-[5-(3-dimethylaminopropylamino)-2-nitrobenzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide

Using an analogous procedure to that described in the second paragraphof the portion of Example 23 which is concerned with the preparation ofstarting materials,4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamidewas reacted with 3-dimethylaminopropylamine to give the title compoundin 76% yield; NMR Spectrum: (DMSOd₆) 1.62-1.74 (m, 2H), 2.12 (s, 6H),2.27 (t, 2H), 3.08-3.13 (m, 4H), 3.18-3.22 (m, 2H), 3.69-3.74 (m, 4H),6.58 (d, 1H), 6.67 (m, 2H), 7.15-7.2 (m, 2H), 7.42 (t, 1H), 7.69 (d,1H), 7.68 (d, 1H), 7.82 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 10.32 (s,1H); Mass Spectrum: M+H⁺ 599.

EXAMPLE 253-[2-amino-5-(3-dimethylaminopropylamino)benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide

Using an analogous procedure to that described in Example 23,4-chloro-3-[5-(3-dimethylaminopropylamino)-2-nitrobenzamido]-N-(3-fluoro-5-morpholinophenyl)benzamidewas reduced to give the title compound; NMR Spectrum: (DMSOd₆) 1.62-1.78(m, 2H), 2.15 (s, 6H), 2.33 (t, 2H), 2.99 (t, 2H), 3.09-3.13 (m, 4H),3.69-3.74 (m, 4H), 6.56 (d, 1H), 6.66 (s, 2H), 6.94 (s, 1H), 7.15-7.22(m, 3H), 7.68 (d, 1H), 7.78 (d, 1H), 8.32 (s, 1H), 10.29 (s, 1H); MassSpectrum: M+H⁺ 569.

EXAMPLE 263-{2-amino-5-[N-(3-methylaminopropyl)-N-methylamino]benzamido}-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide

Using an analogous procedure to that described in Example 23,4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-{5-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamido}benzamidewas reduced to give the title compound; Mass Spectrum: M+H⁺ 569 and 571.

The starting material was prepared by the reaction of4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamidewith N-(3-methylaminopropyl)-N-methylamine using an analogous procedureto that described in the second paragraph of the portion of Example 23which is concerned with the preparation of starting materials; NMRSpectrum: (DMSOd₆) 1.62-1.74 (m, 2H), 2.25 (s, 3H), 2.46-2.49 (m, 2H),3.07 (s, 3H), 3.12 (t, 2H), 3.55 (t, 2H), 3.69-3.74 (m, 4H), 6.58 (d,1H), 6.79 (s, 1H), 6.86 (d, 1H), 7.16-7.2 (m, 2H), 7.69 (d, 1H), 7.82(d, 1H), 8.12 (s, 1H); Mass Spectrum: M+H⁺ 599.

EXAMPLE 273-{2-amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido}-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide

Using an analogous procedure to that described in Example 23,4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-{5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamido}benzamidewas reduced to give the title compound; NMR Spectrum: (DMSOd₆) 1.54-1.62(m, 2H), 2.1 (s, 6H), 2.18-2.22 (m, 2H), 2.77 (s, 3H), 3.09-3.16 (m,4H), 3.18-3.22 (m, 2H), 3.7-3.74 (m, 4H), 6.57 (d, 1H), 6.7 (d, 1H),6.84 (d, 1H), 7.08-7.24 (m, 3H), 7.7 (d, 1H), 7.8 (d, 1H), 8.27 (s, 1H);Mass Spectrum: M+H⁺ 583.

The starting material was prepared by the reaction of4-chloro-3-(5-chloro2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide withN-(3-dimethylaminopropyl)-N-methylamine using an analogous procedure tothat described in the second paragraph of the portion of Example 23which is concerned with the preparation of starting materials; NMRSpectrum: (DMSOd₄) 1.62-1.74 (in, 2H), 2.12 (s, 6H), 2.21 (t, 2H), 3.08(s, 3H), 3.1-3.13 (m, 4H), 3.52 (t, 2H), 3.71-3.74 (m, 4H), 6.68 (d,1H), 6.78 (s, 1H), 6.84 (d, 1H), 7.16-7.20 (m, 2H), 7.68 (d, 1H), 7.82(d, 1H), 8.04 (d, 1H), 8.31 (s, 1H); Mass Spectrum: M+H⁺ 613 and 615.

EXAMPLE 28

Using an analogous procedure to that described in Example 1 or 2, theappropriate benzoyl chloride (prepared by reaction of the correspondingbenzoic acid with oxalyl chloride using an analogous procedure to thatdescribed in the first part of the portion of Example 1 which isconcerned with the preparation of starting materials) was reacted withthe appropriate aniline to give the compounds described in Table II.

TABLE II

No. (R¹)_(m) R³ R Method Note 1 2,4-dimethoxy methyl 3-dimethylamino Ex.2 (a) 2 3,4-diethoxy methyl 3-dimethylamino Ex. 1 (b) 34-(2-ethoxyethoxy) methyl 3-dimethylamino Ex. 1 (c) 4 3,4-dimethoxymethyl 3-morpholino Ex. 1 (d) 5 3,4,5-trimethoxy methyl 3-morpholino Ex.1 (e) 6 3-chloromethyl methyl 3-morpholino Ex. 1 (f) 7 4-chloromethylmethyl 3-morpholino Ex. 1 (g) 8 3-chloromethyl chloro3-fluoro-5-morpholino Ex. 1 (h) 9 4-chloromethyl chloro3-fluoro-5-morpholino Ex. 1 (i) 10 3-chloromethyl methyl3-fluoro-5-pyrrolidin-1-yl Ex. 1 (j) 11 4-chloromethyl methyl3-fluoro-5-pyrrolidin-1-yl Ex. 1 (k) Notes (a) The product was purifiedby column chromatography on an ion exchange column (isolute SCX columnfrom International Sorbent Technology Limited, Hengoed, Mid-Glamorgan,UK) using a 99:1 mixture of methanol and a saturated aqueous ammoniumhydroxide solution as eluent and gave the following data: NMR Spectrum:(DMSOd₆) 2.4(s, 3H), 2.98(s, 6H), 3.89(s, 3H), 4.07(s, 3H), 6.52(d, 1H),6.56(s, 1H), 6.69(d, 1H), 6.94(d, 1H), 7.12(m, 2H), 7.33(d, 1H), 7.7(d,1H), 7.96(br s, 1H), 8.29(d, 1H), 8.81(s, 1H), 9.83 (br s, 1H); MassSpectrum: M + H⁺ 434. (b) The product gave the following data: MassSpectrum: M + H⁺ 462. (c) The reaction product was triturated underdiethyl ether and the solid so obtained was dried under vacuum at 40° C.The resultant product gave the following data: NMR Spectrum: (DMSOd₆)1.12(t, 3H), 2.28(s, 3H), 2.87(s, 6H), 3.5(m, 2H), 3.71(m, 2H), 7.21(d,1H), 4.20(m, 2H), 6.43(d, 1H), 7.12(m, 5H); 7.4(d, 1H), 7.9(d, 1H);7.95(m, 3H), 9.84(br s, 1H), 10.05(br s, 1H); Mass Spectrum: M + H⁺ 462.(d) The product gave the following data: NMR Spectrum: (DMSOd₆)2.3(s,3H), 3.05-3.1(m, 4H), 3.7-3.75(m, 4H), 3.85(s, 6H), 6.65-6.7(m, 1H),7.05-7.2(m, 2H), 7.25-7.3(m, 1H), 7.35-7.45(m, 2H), 7.55-7.6(m, 1H),7.6-7.7(m, 1H), 7.75-7.8(m, 1H), 7.95(s, 1H), 9.9(s, 1H), 10.0-10.02(s,1H); Mass Spectrum: M + H⁺ 476. (e) The product gave the following data:NMR Spectrum: (DMSOd₆)2.3(s, 3H), 3.05-3.1(m, 4H), 3.7-3.75(m, 7H),3.85(s, 6H), 6.65-6.75(m,1H), 7.17(t, 1H), 7.3-7.5(m, 5H), 7.75-7.85(m,1H), 7.85(s, 1H), 10.0(s,1H), 10.01-10.03(s, 1H); Mass Spectrum: M + H⁺506. (f) The product gave the following data: NMR Spectrum:(CDCl₃)2.4(s, 3H), 3.1-3.2(m, 4H), 3.7-3.9(m, 4H), 4.65(s, 2H),6.65-6.75(m, 1H), 7.0-7.05(m, 1H), 7.25(t, 1H), 7.35(d, 1H),7.45-7.75(m, 4H), 7.95(s, 2H), 8.15-8.2(m, 1H), 8.3(s, 1H); MassSpectrum: M + H⁺ 464. (g) The product gave the following data: MassSpectrum: M + H⁺ 464. (h) The reaction mixture was evaporated and theresidue was triturated under water. The solid so obtained was washedwith one equivalent of dilute aqueous hydrochloric acid and dried undervacuum at 40° C. The resultant product gave the following data: NMRSpectrum: (DMSOd₆)3.11(m, 4H), 3.72(m, 4H), 4.86(s, 2H), 6.54(d, 1H),7.14(s, 1H), 7.19(d, 1H), 7.56(t, 1H), 7.71(m, 2H), 7.87(d, 1H), 7.97(d,1H), 8.06(s, 1H), 8.14(s, 1H), 10.3(br s, 2H); Mass Spectrum: M + H⁺502. (i) The reaction mixture was evaporated and the residue wastriturated under water. The solid so obtained was washed with oneequivalent of dilute aqueous hydrochloric acid and dried under vacuum at40° C. The resultant product gave the following data: NMR Spectrum:(DMSOd₆)3.11(m, 4H), 3.72(m, 4H), 4.84(s, 2H), 6.54(d, 1H), 7.15(s, 1H),7.2(d, 1H), 7.6(d, 2H), 7.72(d 1H), 7.87(d, 1H), 8.0(d, 2H), 8.15(s,1H), 10.26(s, 1H), 10.31(s, 1H); Mass Spectrum: M + H⁺ 502. (j) Theproduct gave the following data: NMR Spectrum: (DMSOd₆)1.94(m, 4H),2.31(s, 3H), 3.2(m, 4H), 4.86(s, 2H), 6.06(d, 1H), 6.8(s, 1H), 7.02(d,1H), 7.43(d, 1H), 7.55(t, 1H), 7.67(d, 1H), 7.79(d, 1H), 7.94(s, 1H),7.97(d, 1H), 8.05(s, 1H), 10.1(m, 2H); Mass Spectrum: M + H⁺ 466.

The 3-amino-N-(3-fluoro-5-pyrrolidin-1-ylphenyl)-4-methylbenzamide usedas a starting material was prepared as follows

A mixture of 3,5-difluoronitrobenzene (20 g) and pyrrolidine (63 ml) wasstirred and heated at 100° C. for 4 hours. The mixture was cooled toambient temperature and poured into water (100 ml). The resultant solidwas isolated, washed in turn with water and with diethyl ether and driedunder vacuum. There was thus obtained3-fluoro-5-pyrrolidin-1-ylnitrobenzene (24 g); NMR Spectrum: (DMSOd₆)1.93-1.98 (m, 4H), 3.25-3.3 (m, 4H), 6.72-6.76 (m, 1H), 7.07-7.15 (m,2H).

A mixture of the material so obtained, 10% palladium-on-carbon (3 g) andmethanol (500 ml) was stirred under an atmosphere pressure of hydrogengas until uptake of hydrogen ceased. The mixture was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography on silica gel using a 10:3 mixture of isohexane and ethylacetate as eluent. There was thus obtained3-fluoro-5-pyrrolidin-1-ylaniline (14.8 g); NMR Spectrum: (DMSOd₆)1.87-1.92 (m, 4H), 3.09-3.14 (m, 4H), 5.04 (s, 2H), 5.47-5.62 (m, 3H).

4-Methyl-3-nitrobenzoyl chloride (14.5 ml) was added to a mixture of3-fluoro-5-pyrrolidin-1-ylaniline (14.8 g), triethylamine (25.2 ml) andmethylene chloride (300 ml) and the resultant mixture was stirred atambient temperature for 18 hours. Water (200 ml) was added and theresultant solid was isolated, washed in turn with water and with diethylether and dried under vacuum. There was thus obtained4-methyl-N-(3-fluoro-5-pyrrolidin-1-yl)-3-nitrobenzamide (19.3 g); NMRSpectrum: (DMSOd₆) 1.92-1.97 (m, 4H), 2.58 (s, 3H), 3.18-3.23 (m, 4H),6.09 (d, 1H), 6.77 (s, 1H), 7.99 (d, 1H), 7.66 (d, 1H), 8.16 (d, 1H)8.53 (s, 1H), 10.33 (s, 1H).

A mixture of the material so obtained, 10% palladium-on-carbon (2 g) andmethanol (300 ml) was stirred under an atmosphere pressure of hydrogengas until uptake of hydrogen ceased. The mixture was filtered and thefiltrate was evaporated. The residue was triturated under a mixture ofdiethyl ether and ethyl acetate. The resultant solid was isolated,washed in turn with water and with diethyl ether and dried under vacuum.There was thus obtained the required starting material (14.4 g); NMRSpectrum: (DMSOd₆) 1.91-1.97 (m, 4H), 2.1 (s, 3H), 3.14-3.21 (m, 4H),5.03 (s, 2H), 6.02 (d, 1H), 6.8 (s, 1H), 6.98-7.06 (m, 3H), 7.13 (s,1H), 9.87 (s, 1H); Mass Spectrum: M+H⁺ 314.

-   (k) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.95    (m, 4H), 2.31 (s, 3H), 3.21 (m, 4H), 4.85 (s, 2H), 6.06 (d, 1H),    6.81 (s, 1H), 7.02 (d, 1H), 7.42 (d, 1H), 7.6 (d, 2H), 7.79 (d, 1H),    7.99 (m, 3H), 10.06 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H⁺ 466.

EXAMPLE 29

Using an analogous procedure to that described in Example 5, anappropriate amino-substituted alkyl chloride was reacted with theappropriate phenol to give the compounds described in Table III.

TABLE III

No. (R¹)_(m) R³ R Note 1 3-(2-diethylaminoethoxy) methyl 3-morpholino(a) 2 3-(3-diethylaminopropoxy) methyl 3-morpholino (b) 33-(2-diisopropylaminoethoxy) methyl 3-morpholino (c) 43-(2-pyrrolidin-1-ylethoxy) methyl 3-morpholino (d) 53-(2-piperidinoethoxy) methyl 3-morpholino (e) 6 3-(3-piperidinopropoxy)methyl 3-morpholino (f) 7 3-(N-methylpiperidin-3-ylmethoxy) methyl3-morpholino (g) 8 3-(2-methylthiazol-4-ylmethoxy) methyl 3-morpholino(h) 9 3-(2-diethylaminoethoxy) chloro 3-fluoro-5-morpholino (i) 103-(2-piperidinoethoxy) chloro 3-fluoro-5-morpholino (j) 113-[2-(N-methylpyrrolidin-2-yl)ethoxy] chloro 3-fluoro-5-morpholino (k)12 3-(N-methylhomopiperidin-4-yloxy) chloro 3-fluoro-5-morpholino (l)Notes (a) The reactants were 2-diethylaminoethyl chloride and3-(3-hydroxybenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide. Theproduct gave the following data: NMR Spectrum: (DMSOd₆)0.97(t, 6H),2.27(s, 3H), 2.55(m, 4H), 2.8(t, 2H), 3.08(t, 4H), 3.72(t, 4H), 4.07(t,2H), 6.68(m, 1H), 7.17(m, 2H), 7.29(d, 1H), 7.4(m, 3H), 7.56(m, 2H),7.78(m, 1H), 7.92(s, 1H), 10.0(s, 1H), 10.02(s, 1H); Mass Spectrum: M +H⁺ 531. (b) The product gave the following data: NMR Spectrum:(DMSOd₆)0.92(t, 6H), 1.92(m, 2H), 2.27(s, 3H), 2.47(m, 6H), 3.06(t, 4H),3.72(t, 4H), 4.04(t, 2H), 6.67(m, 1H), 7.17(m, 2H), 7.28(m, 1H), 7.41(m,3H), 7.55(m, 2H), 7.78(m, 1H), 7.92(s, 1H), 10.0(s, 1H), 10.02(s, 1H);Mass Spectrum: M + H⁺ 545. (c) The product gave the following data: NMRSpectrum: (DMSOd₆)0.99(m, 12H), 2.27(s, 3H), 2.78(m, 2H), 3.04(m, 6H),3.74(br s, 4H), 3.95(t, 2H), 6.68(d, 1H), 7.15(m, 2H), 7.28(m, 1H),7.4(m, 3H), 7.55(m, 2H), 7.79(d, 1H), 7.92(s, 1H), 10.0(s, 1H), 10.01(s,1H); Mass Spectrum: M + H⁺ 559. (d) The product gave the following data:NMR Spectrum: (DMSOd₆)1.64(m, 4H), 2.28(s, 3H), 2.5(m, 4H), 2.81(t, 3H),3.05(t, 4H), 3.73(t, 4H), 4.16(t, 2H), 6.66(m, 1H), 7.17(m, 2H), 7.28(d,1H), 7.4(m, 3H), 7.57(m, 2H), 7.79(m, 1H), 7.93(s, 1H), 10.0(s, 1H),10.02(s, 1H); Mass Spectrum: M + H⁺ 529. (e) The product gave thefollowing data: NMR Spectrum: (DMSOd₆)1.36(m, 2H), 1.49(m, 4H), 2.17(s,3H), 2.43(t, 4H), 2.64(t, 2H), 3.06(t, 4H), 3.73(t, 4H), 4.12(t, 2H),6.66(m, 1H), 7.16(m, 2H), 7.28(d, 1H), 7.4(m, 3H), 7.56(m, 2H), 7.78(m,1H), 7.91(s, 1H), 10.0(s, 1H), 10.02(s, 1H); Mass Spectrum: M + H⁺ 543.(f) The product gave the following data: NMR Spectrum: (DMSOd₆)1.36(m,2H), 1.46(m, 4H), 1.84(m, 2H), 2.34(br m, 9H), 3.05(t, 4H), 3.72(t, 4H),4.06(t, 2H), 6.67(m, 1H), 7.16(m, 2H), 7.29(d, 1H), 7.41(m, 3H), 7.55(m,2H), 7.78(d, 1H), 7.92(s, 1H), 10.0(s, 1H), 10.02(s, 1H); Mass Spectrum:M + H⁺ 557. (g) The product gave the following data: NMR Spectrum:(DMSOd₆)1.09(m, 1H), 1.7(br m, 6H), 2.16(s, 3H), 2.28(s, 3H), 2.41(m,1H), 2.81(d, 1H), 3.06(t, 4H), 3.72(t, 4H), 3.92(m, 2H), 6.67(d, 1H),7.17(m, 2H), 7.3(d, 1H), 7.41(m, 3H), 7.55(m, 2H), 7.79(d, 1H), 7.93(s,1H), 10.0(s, 1H), 10.02(s, 1H); Mass Spectrum: M + H⁺ 543. (h) Theproduct gave the following data: NMR Spectrum: (DMSOd₆)2.27(s, 3H),2.63(s, 3H), 3.05(t, 4H), 3.71(t, 4H), 5.19(s, 2H), 6.66(m, 1H), 7.17(t,1H), 7.24(m, 2H), 7.41(m, 3H), 7.59(m, 3H), 7.94(s, 1H), 10.0(s, 1H),10.02(s, 1H); Mass Spectrum: M + H⁺ 543. (i) The reactants were2-diethylaminoethyl chloride and4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-(3-hydroxybenzamido)benzamide.The product gave the following data: NMR Spectrum: (DMSOd₆)0.96(t, 6H),2.55(m, 4H), 2.79(t, 2H), 3.09(t, 4H), 3.7(t, 4H), 4.08(t, 2H), 6.53(d,1H), 7.18(m, 3H), 7.43(t, 1H), 7.57(m, 2H), 7.71(d, 1H), 7.83(m, 1H),8.15(d, 1H), 10.19(s, 1H), 10.29(s, 1H); Mass Spectrum: M + H⁺ 569. (j)The product gave the following data: NMR Spectrum: (DMSOd₆)1.35(d, 2H),1.48(m, 4H), 2.42(m, 4H), 2.65(t, 2H), 3.1(t, 4H), 3.7(t, 4H), 4.13(t,2H), 6.52(d, 1H), 7.18(m, 3H), 7.43(t, 1H), 7.55(m, 2H), 7.7(d, 1H),7.84(m, 1H), 8.15(d, 1H), 10.18(s, 1H), 10.29(s, 1H); Mass Spectrum: M +H⁺ 581. (k) The reactants were 2-(N-methylpyrrolidin-2-yl)ethyl chlorideand4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-(3-hydroxybenzamido)benzamide.The reaction product was purified by column chromatography on silica gelusing increasingly polar mixtures of methylene chloride and methanol aseluent. The product gave the following data: NMR Spectrum:(DMSOd₆)1.5(br m, 4H), 1.9(m, 1H), 2.05(m, 3H), 2.22(s, 3H), 2.93(m,1H), 3.09(t, 4H), 3.71(t, 4H), 4.08(t, 2H), 6.54(dm, 1H), 7.18(m, 2H),7.42(t, 1H), 7.55(m, 2H), 7.7(d, 1H), 7.86(d, 1H), 8.12(d, 1H), 10.19(s,1H), 10.29(s, 1H); Mass Spectrum: M + H⁺ 581. (l) As for Example 29(11),the reactants were 2-(N-methylpyrrolidin-2-yl)ethyl chloride and4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-(3-hydroxybenzamido)benzamideand the reaction product was purified by column chromatography on silicagel using increasingly polar mixtures of methylene chloride and methanolas eluent. The compound of Example 29(11) was eluted first. On furtherelution the isomeric compound of Example 29(12) was eluted. This productgave the following data: NMR Spectrum: (DMSOd₆ )1.57(m, 1H), 1.78(br m,3H), 2.04(m, 2H), 2.23(s, 3H), 2.6(br m, 4H), 3.1(t, 3H), 3.71(t, 4H),4.66(t, 1H), 6.53(m, 1H), 7.11(m, 2H), 7.2(d, 1H), 7.42(t, 1H), 7.5(m,1H), 7.7(d, 1H), 7.85(m, 1H), 8.13(d, 1H), 10.17(s, 1H), 10.29(s, 1H);Mass Spectrum: M + H⁺ 581.

EXAMPLE 304-methyl-3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-N-(3-morpholinophenyl)benzamide

N-Methylpiperazine (0.036 g) was added to a mixture of3-(3-chloromethylbenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide(0.15 g), potassium carbonate (0.09 g) and acetone (5 ml) and theresultant mixture was stirred and heated to 60° C. for 16 hours. Themixture was evaporated and the residue was partitioned between methylenechloride and a saturated aqueous sodium bicarbonate solution. Theorganic phase was dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica gel usingmethanol as eluent. The product so obtained was dissolved in ethylacetate and precipitated by the addition of isohexane. There was thusobtained the title compound (0.071 g); NMR Spectrum: (DMSOd₆) 2.1 (s,3H), 2.3 (s, 3H), 2.2-2.4 (m, 8H), 3.1 (t, 4H), 3.55 (s, 2H), 3.75 (t,4H), 6.65-6.7 (m, 1H), 7.18 (t, 1H), 7.3-7.35 (m, 1H), 7.38-7.55 (m,4H), 7.78-7.8 (m, 1H), 7.85-7.9 (m, 2H), 7.95 (s, 1H); Mass Spectrum:M+H⁺ 528.

EXAMPLE 31

Using an analogous procedure to that described in Example 30, theappropriate chloromethyl-substituted benzamide was reacted with theappropriate amine to give the compounds described in Table IV.

TABLE IV

No. (R¹)_(m) R³ R Note 1 3-(4-methylhomopiperazin-1-ylmethyl) methyl3-morpholino (a) 2 3-diethylaminomethyl methyl 3-morpholino (b) 33-(2-morpholinoethylaminomethyl) methyl 3-morpholino (c) 44-diethylaminomethyl methyl 3-morpholino (d) 54-(4-methylpiperazin-1-ylmethyl) methyl 3-morpholino (e) 64-(4-methylhomopiperazin-1-ylmethyl) methyl 3-morpholino (f) 74-(2-morpholinoethylaminomethyl) methyl 3 -morpholino (g) 83-morpholinomethyl methyl 3-fluoro-5-pyrrolidin-1-yl (h) 93-piperazin-1-ylmethyl methyl 3-fluoro-5-pyrrolidin-1-yl (i) 103-(4-methylpiperazin-1-ylmethyl) methyl 3-fluoro-5-pyrrolidin-1-yl (j)11 3-(4-isopropylpiperazin-1-ylmethyl) methyl 3-fluoro-5-pyrrolidin-l-yl(k) 12 3-(4-methylhomopiperazin-1-ylmethyl) methyl3-fluoro-5-pyrrolidin-1-yl (1) 13 3-(3-hydroxypyrrolidin-1-ylmethyl)methyl 3-fluoro-5-pyrrolidin-1-yl (m) 14 3-[2-(N-dimethylaminoethyl)-methyl 3-fluoro-5-pyrrolidin-1-yl (n) N-methylaminomethyl] 153-(3-dimethylamino-2,2- methyl 3-fluoro-5-pyrrolidin-1-yl (o)dimethylpropylaminomethyl) 16 3-[3-(N-dimethylaminopropyl)- methyl3-fluoro-5-pyrrolidin-1-yl (p) N-methylaminomethyl] 173-(2-methoxyethylaminomethyl) methyl 3-fluoro-5-pyrroLidin-1-yl (q) 183-(3-morpholinopropylaminomethyl) methyl 3-fluoro-5-pyrrolidm-1-yl (r)19 3-(N-butyl-N-methylaminomethyl) methyl 3-fluoro-5-pyrrolidin-1-yl (s)20 4-morpholinomethyl methyl 3-fluoro-5-pyrrolidin-1-yl (t) 214-(4-methylpiperazin-1-ylmethyl) methyl 3-fluoro-5-pyrrolidin-1-yl (u)22 4-(4-isopropylpiperazin-1-ylmethyl) methyl 3-fluoro-5-pyrrolidin-1-yl(v) 23 4-(4-methylhomopiperazin-1-ylmethyl) methyl3-fluoro-5-pyrrolidin-1-yl (w) 24 4-(3-hydroxypyrrolidin-1-ylmethyl)methyl 3-fluoro-5-pyrrolidin-1-yl (x) 25 4-[2-(N-dimethylaminoethyl)-methyl 3-fluoro-5-pyrrolidin-1-yl (y) N-methylaminomethyl] 264-(3-dimethylamino-2,2- methyl 3-fluoro-5-pyrrolidin-1-yl (z)dimethylpropylaminomethyl) 27 4-[3-(N-dimethylaminopropyl)- methyl3-fluoro-5-pyrrolidin-1-yl (aa) N-methylaminomethyl] 284-(2-methoxyethylaminomethyl) methyl 3-fluoro-5-pyrrolidin-1-yl (bb) 294-(3-morpholinopropylaminomethyl) methyl 3-fluoro-5-pyrrolidin-1-yl (cc)30 4-diethylaminomethyl methyl 3-fluoro-5-pyrrolidin-1-yl (dd) 314-(N-butyl-N-methylaminomethyl) methyl 3-fluoro-5-pyrrolidin-1-yl (ee)32 3-morpholinomethyl chloro 3-fluoro-5-morpholino (ff) 333-piperazin-1-ylmethyl chloro 3-fluoro-5-morpholino (gg) 343-(4-methylpiperazin-1-ylmethyl) chloro 3-fluoro-5-morpholino (hh) 353-(4-isopropylpiperazin-1-ylmethyl) chloro 3-fluoro-5-morpholino (ii) 363-(4-methylhomopiperazin-1-ylmethyl) chloro 3-fluoro-5-morpholino (jj)37 3-(3-hydroxypyrrolidin-1-ylmethyl) chloro 3-fluoro-5-morpholino (kk)38 3-[2-(N-dimethylaminoethyl)- chloro 3-fluoro-5-morpholino (ll)N-methylaminomethyl] 39 3-(3-dimethylamino-2,2- chloro3-fluoro-5-morpholino (mm) dimethylpropylaminomethyl) 403-[3-(N-dimethylaminopropyl)- chloro 3-fluoro-5-morpholino (nn)N-methylaminomethyl] 41 3-(2-methoxyethylaminomethyl) chloro3-fluoro-5-morpholino (oo) 42 3-(3-morpholinopropylaminomethyl) chloro3-fluoro-5-morpholino (pp) 43 3-(N-butyl-N-methylaminomethyl) chloro3-fluoro-5-morpholmo (qq) 44 4-morpholinomethyl chloro3-fluoro-5-morpholino (rr) 45 4-(4-methylpiperazin-1-ylmethyl) chloro3-fluoro-5-morpholino (ss) 46 4-(4-methylhomopiperazin-1-ylmethyl)chloro 3-fluoro-5-morpholino (tt) 47 4-(3-hydroxypyrrolidin-1-ylmethyl)chloro 3-fluoro-5-morpholino (uu) 48 4-[2-(N-dimethylaminoethyl)- chloro3-fluoro-5-morpholino (vv) N-methylaminomethyl] 494-(3-dimethylamino-2,2- chloro 3-fluoro-5-morpholino (ww)dimethylpropylaminomethyl) 50 4-[3-(N-dimethylaminopropyl)- chloro3-fluoro-5-morpholino (xx) N-methylaminomethyl] 514-(2-methoxyethylaminomethyl) chloro 3-fluoro-5-morpholino (yy) 524-(3-morpholinopropylaminomethyl) chloro 3-fluoro-5-morpholino (zz) 534-diethylaminomethyl chloro 3-fluoro-5-morpholino (aaa) 544-(N-butyl-N-methylaminomethyl) chloro 3-fluoro-5-morpholino (bbb) Notes(a) The product gave the following data: NMR Spectrum: (CDCl₃)1.8-1.9(m,2H), 2.37(s, 3H), 2.4(s, 3H), 2.6-2.8(m, 8H), 3.2(t, 4H), 3.75(s, 1H),3.85(t, 4H), 6.65-6.75(m, 1H), 7.0-7.05(m, 1H), 7.22(t, 1H), 7.35(d,1H), 7.45-7.5(m, 2H), 7.55-7.6(m, 1H), 7.7-7.75(m, 1H), 7.75-7.8(m, 1H),7.85-7.95(m, 2H), 8.07(s, 1H), 8.45(s, 1H); Mass Spectrum: M + H⁺ 542.(b) The product gave the following data: NMR Spectrum: M + H⁺ 501. (c)The product gave the following data: NMR Spectrum: (DMSOd₆)2.25-2.4(m,9H), 2.55-2.65(m, 2H), 3.05-3.15(m, 4H), 3.5-3.6(m, 4H), 3.7-3.8(m, 6H),6.65-6.75(m, 1H), 7.18(t, 1H), 7.3-7.35(m, 1H), 7.4-7.6(m, 4H),7.75-7.8(m, 1H), 7.8-7.9(m, 1H), 7.95(s, 2H), 10.0-10.04(br d, 2H); MassSpectrum: M + H⁺ 558. (d) The product gave the following data: NMRSpectrum: (DMSOd₆)0.9-1.0(m, 6H), 2.3(s, 3H), 2.4-2.6(m, 4H), 3.0-3.1(m,4H), 3.5-3.7(m, 2H), 3.7-3.8(m, 4H), 6.65-6.75(m, 1H), 7.2(t, 1H),7.25-7.3(m, 1H), 7.35-7.55(m, 4H), 7.75-7.8(m, 1H), 7.9-8.0(m, 3H),10.0(s, 1H), 10.02(br s, 1H); Mass Spectrum: M + H⁺ 501. (e) The productgave the following data: NMR Spectrum: (DMSOd₆)2.1(s, 3H), 2.2-2.45(m,11H), 3.05(t, 4H), 3.55(s, 2H), 3.75(t, 4H), 6.65-6.75(m, 1H), 7.15(t,1H), 7.28-7.32(m, 1H), 7.35-7.48(m, 4H), 7.75-7.8(m, 1H), 7.95-8.0(m,3H), 10.0(s, 1H), 10.03(s, 1H); Mass Spectrum: M + H⁺ 528. (f) Theproduct gave the following data: NMR Spectrum: (DMSOd₆)1.65-1.75(m, 2H),2.25(s, 3H), 2.3(s, 3H), 2.5-2.7(m, 8H), 3.05-3.15(m, 4H), 3.68(s, 2H),3.7-3.8(m, 4H), 6.65-6.75(m, 1H), 7.17(t, 1H), 7.30-7.35(m, 1H),7.4-7.5(m, 4H), 7.75-7.8(m, 1H), 7.9-8.0(m, 3H), 10.03(br s, 1H); MassSpectrum: M + H⁺ 542. (g) The product gave the following data: NMRSpectrum: (DMSOd₆)2.25-2.4(m, 9H), 2.58(t, 2H), 3.05(t, 4H), 3.55(t,4H), 3.72(t, 4H), 3.75(s, 2H), 6.65-6.75(m, 1H), 7.17(t, 1H),7.25-7.3(m, 1H), 7.35-7.5(m, 4H), 7.75-7.8(m, 1H), 7.9-8.0(m, 3H),10.0(s, 1H), 10.03(br s, 1H); Mass Spectrum: M + H⁺ 558. (h) The productgave the following data: NMR Spectrum: M + H⁺ 517. (i) The product gavethe following data: NMR Spectrum: M + H⁺ 516. (j) The product gave thefollowing data: NMR Spectrum: M + H⁺ 530. (k) The product gave thefollowing data: NMR Spectrum: M + H⁺ 558. (l) The product gave thefollowing data: NMR Spectrum: M + H⁺ 544. (m) The product gave thefollowing data: NMR Spectrum: M + H⁺ 517. (n) The product gave thefollowing data: NMR Spectrum: M + H⁺ 532. (o) The product gave thefollowing data: NMR Spectrum: M + H⁺ 560. (p) The product gave thefollowing data: NMR Spectrum: M + H⁺ 546. (q) The product gave thefollowing data: NMR Spectrum: M + H⁺ 505. (r) The product gave thefollowing data: NMR Spectrum: M + H⁺ 574. (s) The product gave thefollowing data: NMR Spectrum: M + H⁺ 517. (t) The product gave thefollowing data: NMR Spectrum: M + H⁺ 517. (u) The product gave thefollowing data: NMR Spectrum: M + H⁺ 530. (v) The product gave thefollowing data: NMR Spectrum: M + H⁺ 558. (w) The product gave thefollowing data: NMR Spectrum: M + H⁺ 544. (x) The product gave thefollowing data: NMR Spectrum: M + H⁺ 517. (y) The product gave thefollowing data: NMR Spectrum: M + H⁺ 532. (z) The product gave thefollowing data: NMR Spectrum: M + H⁺ 560. (aa) The product gave thefollowing data: NMR Spectrum: M + H⁺ 546. (bb) The product gave thefollowing data: NMR Spectrum: M + H⁺ 505. (cc) The product gave thefollowing data: NMR Spectrum: M + H⁺ 574. (dd) Diethylammonium chloridewas used as the source of the amine. An additional equivalent ofpotassium carbonate was added to neutralise the ammonium salt. Theproduct gave the following data: NMR Spectrum: M + H⁺ 503. (ee) Theproduct gave the following data: NMR Spectrum: M + H⁺ 517. (ff) Theproduct gave the following data: NMR Spectrum: (DMSOd₆)2.37(m, 4H),3.11(m, 4H), 3.54(s, 2H), 3.57(m, 4H), 3.72(m, 4H), 6.54(d, 1H), 7.13(s,1H), 7.2(d, 1H), 7.5(m, 2H), 7.72(d, 1H), 7.85(m, 3H), 8.14(s, 1H),10.21(s, 1H), 10.29(s, 1H); Mass Spectrum: M + H⁺ 553. (gg) The productgave the following data: NMR Spectrum: (DMSOd₆)2.3(m, 4H), 2.68(m, 4H),3.11(m, 4H), 3.5(s, 2H), 3.72(m, 4H), 6.54(d, 1H), 7.13(s, 1H), 7.19(d,1H), 7.5(m, 2H), 7.72(d, 1H), 7.87(m, 3H), 8.15(s, 1H), 10.2(s,1H)10.29(s, 1H); Mass Spectrum: M + H⁺ 552. (hh) The product gave thefollowing data: NMR Spectrum: M + H⁺ 566. (ii) The product gave thefollowing data: NMR Spectrum: M + H⁺ 594. (jj) The product gave thefollowing data: NMR Spectrum: M + H⁺ 580. (kk) The product gave thefollowing data: NMR Spectrum: M + H⁺ 553. (ll) The product gave thefollowing data: NMR Spectrum: M + H⁺ 568. (mm) The product gave thefollowing data: NMR Spectrum: M + H⁺ 596. (nn) The product gave thefollowing data: NMR Spectrum: M + H⁺ 582. (oo) The product gave thefollowing data: NMR Spectrum: M + H⁺ 541. (pp) The product gave thefollowing data: NMR Spectrum: M + H⁺ 610. (qq) The product gave thefollowing data: NMR Spectrum: M + H⁺ 553. (rr) The product gave thefollowing data: NMR Spectrum: (DMSOd₆)2.37(m, 4H), 3.11(m, 4H), 3.54(s,2H), 3.58(m, 4H), 3.72(m, 4H), 6.54(d, 1H), 7.14(s, 1H), 7.19(d, 1H),7.47(d, 2H), 7.72(d, 1H), 7.85(d, 1H), 7.96(d, 2H), 8.14(s, 1H),10.16(s, 1H), 10.29(s, 1H); Mass Spectrum: M + H⁺ 553. (ss) The productgave the following data: NMR Spectrum: M + H⁺ 566. (tt) The product gavethe following data: NMR Spectrum: M + H⁺ 580. (uu) The product gave thefollowing data: NMR Spectrum: M + H⁺ 553. (vv) The product gave thefollowing data: NMR Spectrum: M + H⁺ 568. (ww) The product gave thefollowing data: NMR Spectrum: M + H⁺ 596. (xx) The product gave thefollowing data: NMR Spectrum: M + H⁺ 582. (yy) The product gave thefollowing data: NMR Spectrum: M + H⁺ 541. (zz) The product gave thefollowing data: NMR Spectrum: M + H⁺ 610. (aaa) Diethylammonium chloridewas used as the source of the amine. An additional equivalent ofpotassium carbonate was added to neutralise the ammonium salt. Theproduct gave the following data: NMR Spectrum: (DMSOd₆)0.98(t, 6H),2.46(peak obscured by solvent), 3.11(m, 4H), 3.6(s, 2H, 3.72(m, 4H),6.54(d, 1H), 7.14(s, 1H), 7.20(d, 1H), 7.47(d, 2H), 7.72(d, 1H), 7.85(d,1H), 7.95(d, 2H), 8.15(s, 1H), 10.14(s, 1H), 10.29(s, 1H); MassSpectrum: M + H⁺ 539. (bbb) The product gave the following data: NMRSpectrum: M + H⁺ 553.

EXAMPLE 324-methyl-N-(3-morpholinophenyl)-3-(6-quinolylcarbonylamino)benzamide

Using an analogous procedure to that described in Example 1,6-quinolylcarbonyl chloride was reacted with3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give the titlecompound; NMR Spectrum: (DMSOd₆) 2.35 (s, 3H), 3.0-3.1 (m, 4H),3.65-3.75 (m, 4H), 6.65-6.7 (m, 1H), 7.17 (t, 1H), 7.3-7.35 (m, 1H),7.38-7.48 (m, 2H), 7.6-7.7 (m, 1H), 7.8-7.85 (m, 1H), 8.0 (s, 1H),8.1-8.15 (m, 1H), 8.3-8.35 (m, 1H), 8.5-8.55 (m, 1H), 8.7 (s, 1H),8.98-9.02 (m, 1H), 10.0-10.1 (br s, 1H), 10.25-10.35 (br s, 1H); MassSpectrum: M+H⁺ 467.

EXAMPLE 334-chloro-3-(6-chloropyrid-3-ylcarbonylamino)-N-(3-fluoro-5-morpholinophenyl)benzamide

A mixture of 6-chloropyrid-3-ylcarbonyl chloride (1.96 g),3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (3 g) andpyridine (20 ml) was stirred and heated to 100° C. for 4 hours. Themixture was cooled to ambient temperature. Water and diethyl ether wereadded. The resultant precipitate was washed with a saturated aqueoussodium bicarbonate solution and with methanol. There was thus obtainedthe title compound (3.8 g); NMR Spectrum: (DMSOd₆) 3.1 (t, 4H), 3.75 (t,4H), 6.52 (d, 1H), 7.1 (s, 1H), 7.2 (d, 1H), 7.6-7.7 (m, 2H), 7.7-7.8(m, 1H), 8.2 (d, 1H), 8.35-8.4 (m, 1H), 8.97 (d, 1H), 10.2-10. 32 (br S,1H); Mass Spectrum: M+H⁺ 489.

EXAMPLE 343-(6-chloropyrid-3-ylcarbonylamino)-4-methyl-N-(3-morpholinophenyl)benzamide

Using an analogous procedure to that described in Example 33,6-chloropyrid-3-ylcarbonyl chloride was reacted with3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give the titlecompound; NMR Spectrum: (DMSOd₆) 2.3 (s, 3H), 3.05 (t, 4H), 3.75 (t,4H), 6.65-6.75 (m, 1H), 7.18 (t, 1H), 7.25-7.3 (m, 1H), 7.3-7.5 (m, 2H),7.7 (d, 1H), 7.75-7.85 (m, 1H), 7.97 (s, 1H), 8.35-8.45 (m, 1H), 9.0 (d,1H), 10.0-10.04 (s, 1H), 10.26-10.29 (s, 1H); Mass Spectrum: M+H⁺ 451.

EXAMPLE 354-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[6-(4-methylpiperazin-1-yl)pyrid-3-ylcarbonylamino]benzamide

A mixture of4-chloro-3-(6-chloropyrid-3-ylcarbonylamino)-N-(3-fluoro-5-morpholinophenyl)benzamide(0.2 g) and N-methylpiperazine (1.5 g) was stirred and heated to 110° C.for 20 hours. The mixture was cooled to ambient temperature. Water wasadded and the mixture was stirred at ambient temperature for 30 minutes.The resultant precipitate was isolated, washed with water and dried.There was thus obtained the title compound (0.18 g); Mass Spectrum: M+H⁺553.

EXAMPLE 36

Using an analogous procedure to that described in Example 35, theappropriate chloropyridine was reacted with the appropriate amine togive the compounds described in Table V.

TABLE V

No. R¹ R³ R Note 1 2-dimethylaminoethylamino methyl 3-morpholino (a) 2N-(2-methylaminoethyl)-N-methylamino methyl 3-morpholino (b) 3N-(2-dimethylaminoethyl)-N-methylamino methyl 3-morpholino (c) 42-amino-2-methylpropylamino methyl 3-morpholino (d) 5 3-aminopropylaminomethyl 3-morpholino (e) 6 N-(3-dimethylaminopropyl)-N- methyl3-morpholino (f) methylamino 7 3-morpholinopropylamino methyl3-morpholino (g) 8 4-aminobutylamino methyl 3-morpholino (h) 94-methylpiperazin-1-yl methyl 3-morpholino (i) 10 homopiperazin-1-ylmethyl 3-morpholino (j) 11 2-dimethylaminoethylamino chloro3-fluoro-5-morpholino (k) 12 N-(2-methylaminoethyl)-N-methylamino chloro3-fluoro-5-morpholino (l) 13 N-(2-dimethylaminoethyl)-N-methylaminochloro 3-fluoro-5-morpholino (m) 14 2-amino-2-methylpropylamino chloro3-fluoro-5-morpholino (n) 15 3-dimethylaminopropylamino chloro3-fluoro-5-morpholino (o) 16 N-(3-methylaminopropyl)-N-methylaminochloro 3-fluoro-5-morpholino (p) 17 N-(3-dimethylaminopropyl)-N- chloro3-fluoro-5-morpholino (q) methylamino 18 3-morpholinopropylamino chloro3-fluoro-5-morpholino (r) 19 4-dimethylaminobutylamino chloro3-fluoro-5-morpholino (s) 20 homopiperazin-1-yl chloro3-fluoro-5-morpholino (t) Notes (a) The product gave the following data:Mass Spectrum: M + H⁺ 503. (b) The product gave the following data: MassSpectrum: M + H⁺ 503. (c) The product gave the following data: MassSpectrum: M + H⁺ 517. (d) The product gave the following data: MassSpectrum: M + H⁺ 503. (e) The product gave the following data: MassSpectrum: M + H⁺ 489. (f) The product gave the following data: MassSpectrum: M + H⁺ 531. (g) The product gave the following data: MassSpectrum: M + H⁺ 559. (h) The product gave the following data: MassSpectrum: M + H⁺ 503. (i) The product gave the following data: MassSpectrum: M + H⁺ 515. (j) The product gave the following data: MassSpectrum: M + H⁺ 515. (k) The product gave the following data: MassSpectrum: M + H⁺ 541. (l) The product gave the following data: MassSpectrum: M + H⁺ 541. (m) The product gave the following data: MassSpectrum: M + H⁺ 555. (n) The product gave the following data: MassSpectrum: M + H⁺ 541. (o) The product gave the following data: MassSpectrum: M + H⁺ 555. (p) The product gave the following data: MassSpectrum: M + H⁺ 555. (q) The product gave the following data: MassSpectrum: M + H⁺ 569. (r) The product gave the following data: MassSpectrum: M + H⁺ 597. (s) The product gave the following data: MassSpectrum: M + H⁺ 569. (t) The product gave the following data: MassSpectrum: M + H⁺ 553.

EXAMPLE 37 Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph•Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh•Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph•Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph•Eur 488.5 Magnesium 1.5(e) Injection I (50 mg/ml) Compound X  5.0% w/v 1 M Sodium hydroxidesolution 15.0% v/v 0.1 M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400  4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X  1.0% w/v Sodium phosphate BP  3.6%w/v 0.1 M Sodium hydroxide solution 15.0% v/v Water for injection to100% (g) Injection III (1 mg/ml, buffered to pH6) Compound X  0.1% w/vSodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol400  3.5% w/v Water for injection to 100% (h) Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate  13.5 Trichlorofluoromethane 910.0Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound X 0.2Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X   2.5Soya lecithin   2.7 Trichlorofluoromethane  67.5 Dichlorodifluoromethane1086.0 Dichlorotetrafluoroethane  191.6 (l) Ointment ml Compound X   40mg Ethanol 300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one  50 μlPropylene glycol to 1 ml Note The above formulations may be obtained byconventional procedures well known in the pharmaceutical art. Thetablets (a)-(c) may be enteric coated by conventional means, for exampleto provide a coating of cellulose acetate phthalate. The aerosolformulations (h)-(k) may be used in conjunction with standard, metereddose aerosol dispensers, and the suspending agents sorbitan trioleateand soya lecithin may be replaced by an alternative suspending agentsuch as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80,polyglycerol oleate or oleic acid.

1. An amide derivative of the Formula I

wherein R³ is (1-6C)alkyl or halogeno; Q is a 5- or 6-memberedmonocyclic heteroaryl ring of a 9- or 10-membered bicyclic heteroarylring with up to 5 ring heteroatoms selected from oxygen, nitrogen andsulphur, which optionally bears 1, 2, 3 or 4 substituents selected fromhydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,(1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy,hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino,(1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,N-(1-6C)alkyl-cyano-(1-6C)alkylamino,N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,N-(1-6C)alklyamino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino,(1-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino,carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,carbamoyl-(2-6C)alkanoylamino,N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl,aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino,arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino,heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy,heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl,heterocyclyl-(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy,heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino,heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl andheterocyclyl-(2-6C)alkanoylamino, and wherein any of the substituents onQ defined hereinbefore which comprise a CH₂ group which is attached to 2carbon atoms or a CH₃ group which is attached to a carbon atom mayoptionally bear on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and heterocyclyl; and wherein any aryl, heteroarylor heterocyclyl group in a substituent on Q may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy,carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryland aryl-(1-6C)alkyl; R² is hydroxy, halogeno, trifluoromethyl, cyano,mercapto, nitro, amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino ordi-[(1-6C)alkyl]amino; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and R⁴ isaryl, aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino,arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino,cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-6C)alkoxy,heteroarylamino, N-(1-6C)alkyl-heteroarylamino,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl or heteroaryl-(2-6C)alkanoylamino, heterocyclyl,heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclylamino,N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl orheterocyclyl-(2-6C)alkanoylamino and R⁴ optionally bears 1, 2, 3 or 4substituents selected from hydroxy, halogeno, trifluoromethyl, cyano,mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-3C)alkylenedioxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,(1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy,hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino,(1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,N-(1-6C)alkyl-cyano-(1-6C)alkylamino,N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,N-(1-6C)alklyamino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino,(1-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino,carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,carbamoyl-(2-6C)alkanoylamino,N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl,aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino,arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino,heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy,heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl,heterocyclyl-(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy,heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino,heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl andheterocyclyl-(2-6C)alkanoylamino, and wherein any of the substituents onR⁴ defined hereinbefore which comprise a CH₂ group which is attached to2 carbon atoms or a CH₃ group which is attached to a carbon atom mayoptionally bear on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and heterocyclyl; and wherein any aryl, heteroarylor heterocyclyl group in a substituent on R⁴ may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy,carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryland aryl-(1-6C)alkyl; or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.
 2. An amide derivative of the Formula Iaccording to claim 1 wherein Q is substituted by a basic substituentselected from the substituents for Q defined in claim 1 and R⁴ is aphenyl or heteroaryl group as defined in claim 1 which also bears abasic substituent selected from the substituents for R⁴ defined inclaim
 1. 3. An amide derivative of the Formula I according to claim 1selected from:N-(3-dimethylaminophenyl)-4-methyl-3-(6-quinolylcarbonylamino)benzamide,4-chloro-N-(3-dimethylaminophenyl)-3-(6-quinolylcarbonylamino)benzamide,and3-[6-(2-amino-2-methylpropylamino)pyrid-3-ylcarbonylamino]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide; or a pharmaceutically-acceptable salt thereof.
 4. An amidederivative of the Formula I according to claim 1 wherein R³ is methyl,ethyl, chloro or bromo; Q is furyl, thienyl, oxazolyl, isoxazolyl,imidazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, indazolyl, quinolyl, isoquinolyl,quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears 1 or2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl,cyano, methyl, ethyl, methoxy and ethoxy; p is 0; q is 0; and R⁴ isphenyl which bears 1 or 2 substituents selected from hydroxy, fluoro,chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy,methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino,acetyl, propionyl, chloromethyl, methoxymethyl, 2-methoxyethyl,methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-chloroethoxy, 3-chloropropoxy, 2-hydroxyethoxy,3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy,3-ethoxypropoxy, cyanomethoxy, carboxymethoxy, methoxycarbonylmethoxy,ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,2-chloroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino,2-ethoxyethylamino, 2-aminoethylamino, 2-methylaminoethylamino,2-ethylaminoethylamino, 2-dimethylaminoethylamino,2-diethylaminoethylamino, N-(2-chloroethyl)-N-methylamino,N-(2-hydroxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-methylamino,N-(2-ethoxyethyl)-N-methylamino, N-(2-aminoethyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, phenyl, benzyl, benzyloxy,2-pyridylmethoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl,piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl,piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy; or a pharmaceutically-acceptable saltthereof.
 5. An amide derivative of the Formula I according to claim 1wherein R³ is methyl or chloro; Q is 3-isoxazolyl, 3-pyridyl or6-quinolyl which optionally bears a substituent selected from chloro andmethyl; p is 0; q is 0; and R⁴ is phenyl which bears a dimethylaminosubstituent; or a pharmaceutically-acceptable salt thereof.
 6. An amidederivative of the Formula I according to claim 1 wherein R³ is methyl orchloro; Q is 3-pyridyl or 4-pyridyl which bears a substituent selectedfrom 2-aminoethylamino, 3-aminopropylamino, 2-amino-2-methylpropylamino,4-aminobutylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 4-methylaminobutylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 4-dimethylaminobutylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(4-ethylaminobutyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(4-dimethylaminobutyl)-N-methylamino, pyrrolidin-1-yl,3-hydroxypyrrolidin-1-yl, morpholino, piperidino, homopiperidino,piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,4-methylhomopiperazin-1-yl, 3-morpholinopropylamino or2-(1-methylpyrrolidin-2-yl)ethylamino; p is 0; q is 0; and R⁴ is phenylwhich is substituted at the 3-position with a substituent selected fromdimethylamino, diethylamino, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and4-methylhomopiperazin-1-yl and R⁴ is optionally substituted with afurther substituent selected from fluoro, chloro, cyano, methyl andtrifluoromethyl; or a pharmaceutically-acceptable salt thereof.
 7. Aprocess for the preparation of an amide derivative of the Formula I, ora pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof,according to claim 1 which comprises :- (a) reacting a benzoic acid ofthe Formula II, or a reactive derivative thereof,

with an amine of the Formula IIIH₂N—(CH₂)_(q)—R⁴  III under standard amide bond forming conditions,wherein variable groups are as defined in claim 1 and wherein anyfunctional group is protected if necessary, and: (i) removing anyprotecting groups; and (ii) optionally forming apharmaceutically-acceptable salt or in-vivo-cleavable ester; (b)reacting an acid of the Formula IV, or an activated derivative thereof,

with an aniline of the Formula VI

under standard amide bond forming conditions as defined hereinbefore,wherein variable groups are as defined in claim 1 and wherein anyfunctional group is protected, if necessary, and: (i) removing anyprotecting groups; (ii) optionally forming a pharmaceutically-acceptablesalt or in-vivo-cleavable ester; (c) for the preparation of a compoundof the Formula I wherein a substituent on Q or R⁴ is (1-6C)alkoxy orsubstituted (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylamino,di-[(1-6C)alkyl]amino or substituted (1-6C)alkylamino orheterocyclyloxy, the alkylation, conveniently in the presence of asuitable base, of an amide derivative of the Formula I wherein asubstituent on Q or R⁴ is hydroxy, mercapto or amino as appropriate; (d)for the preparation of a compound of the Formula I wherein a substituenton Q or R⁴ is (1-6C)alkanoylamino or substituted (2-6C)alkanoylamino,the acylation of a compound of the Formula I wherein a substituent on Qor R⁴ is amino; (e) for the preparation of a compound of the Formula Iwherein a substituent on Q or R⁴ is (1-6C)alkanesulphonylamino, thereaction of a compound of the Formula I wherein a substituent on Q or R⁴is amino with a (1-6C)alkanesulphonic acid, or an activated derivativethereof; (f) for the preparation of a compound of the Formula I whereina substituent on Q or R⁴ is carboxy, carboxy-(1-6C)alkyl,carboxy-(1-6C)alkoxy, carboxy-(1-6C)alkylamino,N-(1-6C)alkyl-carboxy-(1-6C)alkylamino or carboxy-(2-6C)alkanoylamino,the cleavage of a compound of the Formula I wherein a substituent on Qor R⁴ is (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl,(1-6C)alkoxycarbonyl-(1-6C)alkoxy,(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino or(1-6C)alkoxycarbonyl-(2-6C)alkanoylamino as appropriate; (g) for thepreparation of a compound of the Formula I wherein a substituent on Q orR⁴ is amino-(1-6C)alkyl, heterocyclyl-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,substituted (2-6C)alkylamino-(1-6C)alkyl or substitutedN-(1-6C)alkyl-(2-6C)alkylamino-(1-6C)alkyl, the reaction of a compoundof the Formula I wherein a substituent on Q or R⁴ is a group of theformula -(1-6C)alkylene-Z wherein Z is a displaceable group with anappropriate amine or heterocyclyl compound; (h) for the preparation of acompound of the Formula I wherein a substituent on Q or R⁴ is amino,heterocyclyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, substituted(1-6C)alkylamino, substituted N-(1-6C)alkyl-(1-6C)alkylamino,substituted (2-6C)alkylamino or substitutedN-(1-6C)alkyl-(2-6C)alkylamino, the reaction of a compound of theFormula I wherein a substituent on Q or R⁴ is a displaceable group Zwith an appropriate amine or heterocyclyl compound; (i) for thepreparation of a compound of the Formula I wherein a substituent on Q orR⁴ is N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, the alkylation,conveniently in the presence of a suitable base, of an amide derivativeof the Formula I wherein a substituent on Q or R⁴ is(1-6C)alkanesulphonylamino; (j) for the preparation of a compound of theFormula I wherein a substituent on Q or R⁴ is ahydroxy-heterocyclyl-(1-6C)alkoxy group, ahydroxy-(1-6C)alkylamino-(2-6C)alkoxy group or ahydroxy-di-[(1-6C)alkyl]amino-(2-6C)alkoxy group, the reaction of acompound of the Formula I wherein a substituent on Q or R⁴ is aepoxy-substituted (1-6C)alkoxy group with a heterocyclyl compound or anappropriate amine; or (k) for the preparation of a compound of theFormula I wherein R² or a substituent on Q or R⁴ is an amino group, thereduction of a compound of the Formula I wherein R² or a substituent onQ or R⁴ is a nitro group.
 8. A pharmaceutical composition whichcomprises an amide derivative of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof,according to any one of claims 1, 2, 3, 4, 5 and 6 in association with apharmaceutically-acceptable diluent or carrier.